Heterocyclic compounds as monoacylglycerol lipase inhibitors

ABSTRACT

The invention provides new heterocyclic compounds having the general formula (I)wherein A, L, X, m, n, R1 and R2 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/844,262, filed Apr. 9, 2020, which is a continuation of InternationalApplication No. PCT/EP2019/071520, filed Aug. 12, 2019, which claimspriority to EP Application No. 18188681.3, filed Aug. 13, 2018, thedisclosure of each of which is incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

The present invention relates to organic compounds useful for therapy orprophylaxis in a mammal, and in particular to monoacylglycerol lipase(MAGL) inhibitors for the treatment or prophylaxis of neuroinflammation,neurodegenerative diseases, pain, cancer, mental disorders, multiplesclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy,anxiety, migraine and/or depression in a mammal.

BACKGROUND OF THE INVENTION

Endocannabinoids (ECs) are signaling lipids that exert their biologicalactions by interacting with cannabinoid receptors (CBRs), CB1 and CB2.They modulate multiple physiological processes includingneuroinflammation, neurodegeneration and tissue regeneration (Iannotti,F. A., et al., Progress in lipid research 2016, 62, 107-28). In thebrain, the main endocannabinoid, 2-arachidonoylglycerol (2-AG), isproduced by diacyglycerol lipases (DAGL) and hydrolyzed by themonoacylglycerol lipase, MAGL. MAGL hydrolyses 85% of 2-AG; theremaining 15% being hydrolysed by ABHD6 and ABDH12 (Nomura, D. K., etal., Science 2011, 334, 809). MAGL is expressed throughout the brain andin most brain cell types, including neurons, astrocytes,oligodendrocytes and microglia cells (Chanda, P. K., et al., Molecularpharmacology 2010, 78, 996; Viader, A., et al., Cell reports 2015, 12,798). 2-AG hydrolysis results in the formation of arachidonic acid (AA),the precursor of prostaglandins (PGs) and leukotrienes (LTs). Oxidativemetabolism of AA is increased in inflamed tissues. There are twoprincipal enzyme pathways of arachidonic acid oxygenation involved ininflammatory processes, the cyclo-oxygenase which produces PGs and the5-lipoxygenase which produces LTs. Of the various cyclooxygenaseproducts formed during inflammation, PGE2 is one of the most important.These products have been detected at sites of inflammation, e.g. in thecerebrospinal fluid of patients suffering from neurodegenerativedisorders and are believed to contribute to inflammatory response anddisease progression.

Mice lacking MAGL (Mgll−/−) exhibit dramatically reduced 2-AG hydrolaseactivity and elevated 2-AG levels in the nervous system while otherarachidonoyl-containing phospho- and neutral lipid species includinganandamide (AEA), as well as other free fatty acids, are unaltered.Conversely, levels of AA and AA-derived prostaglandins and othereicosanoids, including prostaglandin E2 (PGE2), D2 (PGD2), F2 (PGF2),and thromboxane B2 (TXB2), are strongly decreased. Phospholipase A₂(PLA₂) enzymes have been viewed as the principal source of AA, butcPLA₂-deficient mice have unaltered AA levels in their brain,reinforcing the key role of MAGL in the brain for AA production andregulation of the brain inflammatory process.

Neuroinflammation is a common pathological change characteristic ofdiseases of the brain including, but not restricted to,neurodegenerative diseases (e.g. multiple sclerosis, Alzheimer'sdisease, Parkinson disease, amyotrophic lateral sclerosis, traumaticbrain injury, neurotoxicity, stroke, epilepsy and mental disorders suchas anxiety and migraine). In the brain, production of eicosanoids andprostaglandins controls the neuroinflammation process.

The pro-inflammatory agent lipopolysaccharide (LPS) produces a robust,time-dependent increase in brain eicosanoids that is markedly blunted inMgll−/− mice. LPS treatment also induces a widespread elevation inpro-inflammatory cytokines including interleukin-1-a (IL-1-a), IL-1b,IL-6, and tumor necrosis factor-a (TNF-α) that is prevented in Mgll−/−mice.

Neuroinflammation is characterized by the activation of the innateimmune cells of the central nervous system, the microglia and theastrocytes. It has been reported that anti-inflammatory drugs cansuppress in preclinical models the activation of glia cells and theprogression of disease including Alzheimer's disease and mutiplesclerosis (Lleo A., Cell Mol Life Sci. 2007, 64, 1403). Importantly,genetic and/or pharmacological disruption of MAGL activity also blocksLPS-induced activation of microglial cells in the brain (Nomura, D. K.,et al., Science 2011, 334, 809).

In addition, genetic and/or pharmacological disruption of MAGL activitywas shown to be protective in several animal models of neurodegenerationincluding, but not restricted to, Alzheimer's disease, Parkinson'sdisease and multiple sclerosis. For example, an irreversible MAGLinhibitor has been widely used in preclinical models ofneuroinflammation and neurodegeneration (Long, J. Z., et al., Naturechemical biology 2009, 5, 37). Systemic injection of such inhibitorrecapitulates the Mgll−/− mice phenotype in the brain, including anincrease in 2-AG levels, a reduction in AA levels and relatedeicosanoids production, as well as the prevention of cytokinesproduction and microglia activation following LPS-inducedneuroinflammation (Nomura, D. K., et al., Science 2011, 334, 809),altogether confirming that MAGL is a druggable target.

Consecutive to the genetic and/or pharmacological disruption of MAGLactivity, the endogenous levels of the MAGL natural substrate in thebrain, 2-AG, are increased. 2-AG has been reported to show beneficialeffects on pain with, for example, anti-nociceptive effects in mice(Ignatowska-Jankowska B. et al., J. Pharmacol. Exp. Ther. 2015, 353,424.) and on mental disorders, such as depression in chronic stressmodels (Zhong P. et al., Neuropsychopharmacology 2014, 39, 1763).

Furthermore, oligodendrocytes (OLs), the myelinating cells of thecentral nervous system, and their precursors (OPCs) express thecannabinoid receptor 2 (CB2) on their membrane. 2-AG is the endogenousligand of CB1 and CB2 receptors. It has been reported that bothcannabinoids and pharmacological inhibition of MAGL attenuate OLs's andOPCs's vulnerability to excitotoxic insults and therefore may beneuroprotective (Bernal-Chico, A., et al., Glia 2015, 63, 163).Additionally, pharmacological inhibition of MAGL increases the number ofmyelinating OLs in the brain of mice, suggesting that MAGL inhibitionmay promote differentiation of OPCs in myelinating OLs in vivo (Alpar,A., et al., Nature communications 2014, 5, 4421). Inhibition of MAGL wasalso shown to promote remyelination and functional recovery in a mousemodel of progressive multiple sclerosis (Feliu A. et al., Journal ofNeuroscience 2017, 37 (35), 8385).

Finally, in recent years, metabolism is talked highly important incancer research, especially the lipid metabolism. Researchers believethat the de novo fatty acid synthesis plays an important role in tumordevelopment. Many studies illustrated that endocannabinoids haveanti-tumorigenic actions, including anti-proliferation, apoptosisinduction and anti-metastatic effects. MAGL as an important decomposingenzyme for both lipid metabolism and the endocannabinoids system,additionally as a part of a gene expression signature, contributes todifferent aspects of tumourigenesis (Qin, H., et al., Cell Biochem.Biophys. 2014, 70, 33; Nomura D K et al., Cell 2009, 140(1), 49-61;Nomura D K et al., Chem. Biol. 2011, 18(7), 846-856).

In conclusion, suppressing the action and/or the activation of MAGL is apromising new therapeutic strategy for the treatment or prevention ofneuroinflammation, neurodegenerative diseases, pain, cancer and mentaldisorders. Furthermore, suppressing the action and/or the activation ofMAGL is a promising new therapeutic strategy for providingneuroprotection and myelin regeneration. Accordingly, there is a highunmet medical need for new MAGL inhibitors.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a compound of formula(I)

-   -   or a pharmaceutically acceptable salt thereof, wherein wherein        A, L, X, m, n, R¹ and R² are as described herein.

In one aspect, the present invention provides a process of manufacturingthe urea compounds of formula (I) described herein, comprising:

-   -   reacting a first amine of formula 1, wherein R¹ is as described        herein, preferably wherein R¹ is hydrogen,

-   -   with a second amine 2, wherein A, L, m, n, X and R² are as        described herein

-   -   in the presence of a base and a urea forming reagent,

to form said compound of formula (I).

In a further aspect, the present invention provides a compound offormula (I) as described herein, when manufactured according to theprocesses described herein.

In a further aspect, the present invention provides a compound offormula (I) as described herein, for use as therapeutically activesubstance.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) as described herein anda therapeutically inert carrier.

In a further aspect, the present invention provides the use of acompound of formula (I) as described herein or of a pharmaceuticalcomposition described herein for inhibiting monoacylglycerol lipase(MAGL) in a mammal.

In a further aspect, the present invention provides the use of acompound of formula (I) as described herein or of a pharmaceuticalcomposition described herein for the treatment or prophylaxis ofneuroinflammation, neurodegenerative diseases, pain, cancer and/ormental disorders in a mammal.

In a further aspect, the present invention provides the use of acompound of formula (I) as described herein or of a pharmaceuticalcomposition described herein for the treatment or prophylaxis ofmultiple sclerosis, Alzheimer's disease, Parkinson's disease,amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity,stroke, epilepsy, anxiety, migraine, depression, hepatocellularcarcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain,chemotherapy induced neuropathy, acute pain, chronic pain and/orspasticity associated with pain in a mammal.

In a further aspect, the present invention provides a compound offormula (I) as described herein or a pharmaceutical compositiondescribed herein for use in a method of inhibiting monoacylglycerollipase in a mammal.

In a further aspect, the present invention provides a compound offormula (I) as described herein or a pharmaceutical compositiondescribed herein for use in the treatment or prophylaxis ofneuroinflammation, neurodegenerative diseases, pain, cancer and/ormental disorders in a mammal.

In a further aspect, the present invention provides a compound offormula (I) as described herein or a pharmaceutical compositiondescribed herein, for use in the treatment or prophylaxis of multiplesclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy,anxiety, migraine, depression, hepatocellular carcinoma, coloncarcinogenesis, ovarian cancer, neuropathic pain, chemotherapy inducedneuropathy, acute pain, chronic pain and/or spasticity associated withpain in a mammal.

In a further aspect, the present invention provides the use of acompound of formula (I) as described herein for the preparation of amedicament for inhibiting monoacylglycerol lipase in a mammal.

In a further aspect, the present invention provides the use of acompound of formula (I) as described herein for the preparation of amedicament for the treatment or prophylaxis of neuroinflammation,neurodegenerative diseases, pain, cancer and/or mental disorders in amammal.

In a further aspect, the present invention provides the use of acompound of formula (I) as described herein for the preparation of amedicament for the treatment or prophylaxis of multiple sclerosis,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety,migraine, depression, hepatocellular carcinoma, colon carcinogenesis,ovarian cancer, neuropathic pain, chemotherapy induced neuropathy, acutepain, chronic pain and/or spasticity associated with pain in a mammal.

In a further aspect, the present invention provides a method forinhibiting monoacylglycerol lipase in a mammal, which method comprisesadministering an effective amount of a compound of formula (I) asdescribed herein or of a pharmaceutical composition described herein tothe mammal.

In a further aspect, the present invention provides a method for thetreatment or prophylaxis of neuroinflammation, neurodegenerativediseases, pain, cancer and/or mental disorders in a mammal, which methodcomprises administering an effective amount of a compound of formula (I)as described herein or of a pharmaceutical composition described hereinto the mammal.

In a further aspect, the present invention provides a method for thetreatment or prophylaxis of multiple sclerosis, Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis, traumatic braininjury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression,hepatocellular carcinoma, colon carcinogenesis, ovarian cancer,neuropathic pain, chemotherapy induced neuropathy, acute pain, chronicpain and/or spasticity associated with pain in a mammal, which methodcomprises administering an effective amount of a compound of formula (I)as described herein or of a pharmaceutical composition described hereinto the mammal.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Features, integers, characteristics, compounds, chemical moieties orgroups described in conjunction with a particular aspect, embodiment orexample of the invention are to be understood to be applicable to anyother aspect, embodiment or example described herein, unlessincompatible therewith. All of the features disclosed in thisspecification (including any accompanying claims, abstract anddrawings), and/or all of the steps of any method or process sodisclosed, may be combined in any combination, except combinations whereat least some of such features and/or steps are mutually exclusive. Theinvention is not restricted to the details of any foregoing embodiments.The invention extends to any novel one, or any novel combination, of thefeatures disclosed in this specification (including any accompanyingclaims, abstract and drawings), or to any novel one, or any novelcombination, of the steps of any method or process so disclosed.

The term “alkyl” refers to a mono- or multivalent, e.g., a mono- orbivalent, linear or branched saturated hydrocarbon group of 1 to 12carbon atoms. In some preferred embodiments, the alkyl group contains 1to 6 carbon atoms (“C₁₋₆-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbonatoms. In other embodiments, the alkyl group contains 1 to 3 carbonatoms, e.g., 1, 2 or 3 carbon atoms. Some non-limiting examples of alkylinclude methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl,sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particularly preferred,yet non-limiting examples of alkyl are methyl and tert-butyl.

The term “alkoxy” refers to an alkyl group, as previously defined,attached to the parent molecular moiety via an oxygen atom. Unlessotherwise specified, the alkoxy group contains 1 to 12 carbon atoms. Insome preferred embodiments, the alkoxy group contains 1 to 6 carbonatoms (“C₁₋₆-alkoxy”). In other embodiments, the alkoxy group contains 1to 4 carbon atoms. In still other embodiments, the alkoxy group contains1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups includemethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy andtert-butoxy. A particularly preferred, yet non-limiting example ofalkoxy is methoxy.

The term “halogen” or “halo” refers to fluoro (F), chloro (Cl), bromo(Br), or iodo (I). Preferably, the term “halogen” or “halo” refers tofluoro (F), chloro (Cl) or bromo (Br). Particularly preferred, yetnon-limiting examples of “halogen” or “halo” are fluoro (F) and chloro(Cl).

The term “cycloalkyl” as used herein refers to a saturated or partlyunsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ringcarbon atoms. In some preferred embodiments, the cycloalkyl group is asaturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms.“Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of twosaturated carbocycles having two carbon atoms in common, i.e., thebridge separating the two rings is either a single bond or a chain ofone or two ring atoms, and to spirocyclic moieties, i.e., the two ringsare connected via one common ring atom. Preferably, the cycloalkyl groupis a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms,e.g., of 3, 4, 5 or 6 carbon atoms. Some non-limiting examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

The terms “heterocyclyl” and “heterocycloalkyl” are used hereininterchangeably and refer to a saturated or partly unsaturated mono- orbicyclic, preferably monocyclic ring system of 3 to 10 ring atoms,preferably 3 to 8 ring atoms, wherein 1, 2, or 3 of said ring atoms areheteroatoms selected from N, O and S, the remaining ring atoms beingcarbon. Preferably, 1 to 2 of said ring atoms are selected from N and O,the remaining ring atoms being carbon. “Bicyclic heterocyclyl” refers toheterocyclic moieties consisting of two cycles having two ring atoms incommon, i.e., the bridge separating the two rings is either a singlebond or a chain of one or two ring atoms, and to spirocyclic moieties,i.e., the two rings are connected via one common ring atom. Somenon-limiting examples of monocyclic heterocyclyl groups includeazetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, 1-piperidyl,2-piperidyl, 3-piperidyl, 4-piperidyl, 2-oxopyrrolidin-1-yl,2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, 5-oxopyrrolidin-3-yl,2-oxo-1-piperidyl, 2-oxo-3-piperidyl, 2-oxo-4-piperidyl,6-oxo-2-piperidyl, 6-oxo-3-piperidyl, morpholino, morpholin-2-yl andmorpholin-3-yl.

The term “aryl” refers to a monocyclic, bicyclic, or tricycliccarbocyclic ring system having a total of 6 to 14 ring members,preferably, 6 to 12 ring members, and more preferably 6 to 10 ringmembers, and wherein at least one ring in the system is aromatic. Somenon-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g.9H-fluoren-9-yl). A particularly preferred, yet non-limiting example ofaryl is phenyl.

The term “heteroaryl” refers to a mono- or multivalent, monocyclic orbicyclic ring system having a total of 5 to 14 ring members, preferably,5 to 12 ring members, and more preferably 5 to 10 ring members, whereinat least one ring in the system is aromatic, and at least one ring inthe system contains one or more heteroatoms. Preferably, “heteroaryl”refers to a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatomsindependently selected from O, S and N. Most preferably, “heteroaryl”refers to a 5-10 membered heteroaryl comprising 1 to 2 heteroatomsindependently selected from O, S and N. Some preferred, yet non-limitingexamples of heteroaryl include thiazolyl (e.g. thiazol-2-yl); oxazolyl(e.g. oxazol-2-yl); 5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl;1,2,4-oxadiazol-5-yl; pyridyl (e.g. 2-pyridyl); pyrazolyl (e.g.pyrazol-1-yl); imidazolyl (e.g. imidazole-1-yl); benzoxazolyl (e.g.benzoxazol-2-yl) and oxazolo[5,4-c]pyridin-2-yl.

The term “hydroxy” refers to an —OH group.

The term “cyano” refers to a —CN (nitrile) group.

The term “haloalkyl” refers to an alkyl group, wherein at least one ofthe hydrogen atoms of the alkyl group has been replaced by a halogenatom, preferably fluoro. Preferably, “haloalkyl” refers to an alkylgroup wherein 1, 2 or 3 hydrogen atoms of the alkyl group have beenreplaced by a halogen atom, most preferably fluoro. Particularlypreferred, yet non-limiting examples of haloalkyl are trifluoromethyl(CF₃) and trifluoroethyl (e.g. 2,2,2-trifluoroethyl).

The term “haloalkoxy” refers to an alkoxy group, wherein at least one ofthe hydrogen atoms of the alkoxy group has been replaced by a halogenatom, preferably fluoro. Preferably, “haloalkoxy” refers to an alkoxygroup wherein 1, 2 or 3 hydrogen atoms of the alkoxy group have beenreplaced by a halogen atom, most preferably fluoro. A particularlypreferred, yet non-limiting example of haloalkoxy is trifluoromethoxy(—OCF₃).

The term “hydroxyalkyl” refers to an alkyl group, wherein at least oneof the hydrogen atoms of the alkyl group has been replaced by a hydroxygroup. Preferably, “hydroxyalkyl” refers to an alkyl group wherein 1, 2or 3 hydrogen atoms, most preferably 1 hydrogen atom of the alkyl grouphave been replaced by a hydroxy group. Preferred, yet non-limitingexamples of hydroxyalkyl are hydroxymethyl and hydroxyethyl (e.g.2-hydroxyethyl). A particularly preferred, yet non-limiting example ofhydroxyalkyl is hydroxymethyl.

The term “haloaryl” refers to an aryl group, wherein at least one of thehydrogen atoms of the aryl group has been replaced by a halogen atom.Preferably, “haloaryl” refers to an aryl group wherein 1, 2 or 3hydrogen atoms, more preferably 1 or 2 hydrogen atoms, most preferably 1hydrogen atom of the aryl group have been replaced by a halogen atom. Aparticularly preferred, yet non-limiting example of haloaryl ischlorophenyl, in particular 4-chlorophenyl.

The term “aryloxy” refers to an aryl group, as previously defined,attached to the parent molecular moiety via an oxygen atom. A preferred,yet non-limiting example of aryloxy is phenoxy.

The term “haloaryloxy” refers to a haloaryl group, as previouslydefined, attached to the parent molecular moiety via an oxygen atom. Apreferred, yet non-limiting example of haloaryloxy is 4-fluorophenoxy.

The term “pharmaceutically acceptable salt” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, in particular hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,N-acetylcystein and the like. In addition these salts may be prepared byaddition of an inorganic base or an organic base to the free acid.

Salts derived from an inorganic base include, but are not limited to,the sodium, potassium, lithium, ammonium, calcium, magnesium salts andthe like. Salts derived from organic bases include, but are not limitedto salts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine, lysine,arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.Particular pharmaceutically acceptable salts of compounds of formula (I)are hydrochloride salts.

The term “pharmaceutically acceptable ester” refers to esters thathydrolyze in vivo and include those that break down readily in the humanbody to leave the parent compound or a salt thereof. Suitable estergroups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Representativeexamples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.Examples of pharmaceutically acceptable prodrug types are described inHiguchi and Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of theA.C.S. Symposium Series, and in Roche, ed., Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press,1987.

The term “protective group” (PG) denotes the group which selectivelyblocks a reactive site in a multifunctional compound such that achemical reaction can be carried out selectively at another unprotectedreactive site in the meaning conventionally associated with it insynthetic chemistry. Protective groups can be removed at the appropriatepoint. Exemplary protective groups are amino-protective groups,carboxy-protective groups or hydroxy-protective groups.

Particular protective groups are the tert-butoxycarbonyl (Boc),benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl(Bn). Further particular protective groups are the tert-butoxycarbonyl(Boc) and the fluorenylmethoxycarbonyl (Fmoc). More particularprotective group is the tert-butoxycarbonyl (Boc). Exemplary protectivegroups and their application in organic synthesis are described, forexample, in “Protective Groups in Organic Chemistry” by T. W. Greene andP. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.

The term “urea forming reagent” refers to a chemical compound that isable to render a first amine to a species that will react with a secondamine, thereby forming an urea derivative. Non-limiting examples of ureaforming reagents include bis(trichloromethyl) carbonate, phosgene,trichloromethyl chloroformate, (4-nitrophenyl)carbonate and1,1′-carbonyldiimidazole. The urea forming reagents described in G.Sartori et al., Green Chemistry 2000, 2, 140 are incorporated herein byreference.

The compounds of formula (I) can contain several asymmetric centers andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereioisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates. In a preferredembodiment, the compound of formula (I) according to the invention is acis-enantiomer of formula (Ia) or (Ib), respectively, as describedherein.

According to the Cahn-Ingold-Prelog Convention, the asymmetric carbonatom can be of the “R” or “S” configuration.

The abbreviation “MAGL” refers to the enzyme monoacylglycerol lipase.The terms “MAGL” and “monoacylglycerol lipase” are used hereininterchangeably.

The term “treatment” as used herein includes: (1) inhibiting the state,disorder or condition (e.g. arresting, reducing or delaying thedevelopment of the disease, or a relapse thereof in case of maintenancetreatment, of at least one clinical or subclinical symptom thereof);and/or (2) relieving the condition (i.e., causing regression of thestate, disorder or condition or at least one of its clinical orsubclinical symptoms). The benefit to a patient to be treated is eitherstatistically significant or at least perceptible to the patient or tothe physician. However, it will be appreciated that when a medicament isadministered to a patient to treat a disease, the outcome may not alwaysbe effective treatment.

The term “prophylaxis” as used herein includes: preventing or delayingthe appearance of clinical symptoms of the state, disorder or conditiondeveloping in a mammal and especially a human that may be afflicted withor predisposed to the state, disorder or condition but does not yetexperience or display clinical or subclinical symptoms of the state,disorder or condition.

The term “neuroinflammation” as used herein relates to acute and chronicinflammation of the nervous tissue, which is the main tissue componentof the two parts of the nervous system; the brain and spinal cord of thecentral nervous system (CNS), and the branching peripheral nerves of theperipheral nervous system (PNS). Chronic neuroinflammation is associatedwith neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease and multiple sclerosis. Acute neuroinflammation usually followsinjury to the central nervous system immediately, e.g., as a result oftraumatic brain injury (TBI).

The term “traumatic brain injury” (“TBI”, also known as “intracranialinjury”), relates to damage to the brain resulting from externalmechanical force, such as rapid acceleration or deceleration, impact,blast waves, or penetration by a projectile.

The term “neurodegenerative diseases” relates to diseases that arerelated to the progressive loss of structure or function of neurons,including death of neurons. Examples of neurodegenerative diseasesinclude, but are not limited to, multiple sclerosis, Alzheimer'sdisease, Parkinson's disease and amyotrophic lateral sclerosis.

The term “mental disorders” (also called mental illnesses or psychiatricdisorders) relates to behavioral or mental patterns that may causesuffering or a poor ability to function in life. Such features may bepersistent, relapsing and remitting, or occur as a single episode.Examples of mental disorders include, but are not limited to, anxietyand depression.

The term “pain” relates to an unpleasant sensory and emotionalexperience associated with actual or potential tissue damage. Examplesof pain include, but are not limited to, nociceptive pain, chronic pain(including idiopathic pain), neuropathic pain including chemotherapyinduced neuropathy, phantom pain and phsychogenic pain. A particularexample of pain is neuropathic pain, which is caused by damage ordisease affecting any part of the nervous system involved in bodilyfeelings (i.e., the somatosensory system). In one embodiment, “pain” isneuropathic pain resulting from amputation or thoracotomy. In oneembodiment, “pain” is chemotherapy induced neuropathy.

The term “neurotoxicity” relates to toxicity in the nervous system. Itoccurs when exposure to natural or artificial toxic substances(neurotoxins) alter the normal activity of the nervous system in such away as to cause damage to nervous tissue. Examples of neurotoxicityinclude, but are not limited to, neurotoxicity resulting from exposureto substances used in chemotherapy, radiation treatment, drug therapies,drug abuse, and organ transplants, as well as exposure to heavy metals,certain foods and food additives, pesticides, industrial and/or cleaningsolvents, cosmetics, and some naturally occurring substances.

The term “cancer” refers to a disease characterized by the presence of aneoplasm or tumor resulting from abnormal uncontrolled growth of cells(such cells being “cancer cells”). As used herein, the term cancerexplicitly includes, but is not limited to, hepatocellular carcinoma,colon carcinogenesis and ovarian cancer.

The term “mammal” as used herein includes both humans and non-humans andincludes but is not limited to humans, non-human primates, canines,felines, murines, bovines, equines, and porcines. In a particularlypreferred embodiment, the term “mammal” refers to humans.

Compounds of the Invention

In a first aspect, the present invention provides a compound of formula(I)

-   -   or a pharmaceutically acceptable salt thereof,    -   wherein:    -   (i) X is C—R³; m is 0 or 1; n is selected from 0, 1 and 2; and L        is selected from —(CH₂)_(p)—, —O—, —OCH₂—, —CH₂O—, —CH₂OCH₂—,        —CF₂CH₂—, and —CH₂CF₂—; or    -   (ii) X is N; m is 1; n is 1 or 2; and L is —(CH₂)_(p)— or        —CF₂CH₂—;    -   p is selected from 1, 2 and 3;    -   A is selected from:        -   (i) aryl substituted with R⁴, R⁵ and R⁶;        -   (ii) heteroaryl substituted with R⁷, R⁸ and R⁹; and        -   (iii) heterocycloalkyl substituted with R¹⁰, R¹¹ and R¹²;    -   R¹ is hydrogen or C₁₋₆-alkyl;    -   R² is selected from hydrogen, C₁₋₆-alkyl and hydroxy-C₁₋₆-alkyl;    -   R³ is selected from hydrogen, halogen, hydroxy, C₁₋₆-alkoxy,        C₁₋₆-alkyl and halo-C1-6-alkyl;    -   each of R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is        independently selected from hydrogen, halogen, cyano, hydroxy,        C₁₋₆-alkyl, halo-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl,        halo-C₁₋₅-alkyl-CH(OH)—, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, SF₅,        CH₃SO₂, C₃₋₁₀-cycloalkyl, C₃₋₁₀-cycloalkyl substituted with R¹³,        heterocycloalkyl, heterocycloalkyl substituted with R¹⁴,        heteroaryl, aryl and haloaryl; and    -   each of R¹³ and R¹⁴ is independently C₁₋₆-alkyl, halo-C₁₋₆-alkyl        or hydroxy.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein the compound of formula (I) is a compound of formula (Ia):

-   -   wherein A, L, X, m, n, R¹ and R² are as defined herein.        Preferably, said compound of formula (Ia) has an enantiomeric        excess (ee) of >80%, more preferably >90%, in particular >99%.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein the compound of formula (I) is a compound of formula (Ib):

-   -   wherein A, L, X, m, n, R¹ and R² are as defined herein.        Preferably, said compound of formula (Ib) has an enantiomeric        excess (ee) of >80%, more preferably >90%, in particular >99%.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein the compound of formula (I) is a compound of formula (Ic):

wherein A, L, X, m, n, R¹ and R² are as defined herein. Preferably, saidcompound of formula (Ic) has an enantiomeric excess (ee) of >800%, morepreferably >90%, in particular >9900.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein the compound of formula (I) is a compound of formula (Id):

wherein A, L, X, m, n, R¹ and R² are as defined herein. Preferably, saidcompound of formula (Id) has an enantiomeric excess (ee) of >80%, morepreferably >90%, in particular >99%.

In one embodiment, there is provided a compound of formula (I) asdescribed herein, wherein when X is C—R³ and R³ is hydroxy or halogen, Lis not —O— or —CH₂O—.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein:

-   -   (i) X is C—R³; m is 0 or 1; n is selected from 0, 1 and 2; and L        is selected from —(CH₂)_(p)—, —O—, —OCH₂—, —CH₂O— and —CH₂OCH₂—;        or    -   (ii) X is N; m and n are both 1; and L is —(CH₂)_(p)—.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein:

-   -   X is C—R³.    -   m and n are both 0; or    -   m and n are both 1; and    -   L is selected from —(CH₂)_(p)—, —O—, —OCH₂— and —CH₂—.

In another preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein:

-   -   X is C—R³.    -   m and n are both 0; or    -   m and n are both 1;    -   L is selected from —(CH₂)_(p)—, —O—, —OCH₂— and —CH₂O—;    -   R³ is selected from hydrogen, C₁₋₆-alkyl and halogen; and    -   p is 1 or 2.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein:

-   -   X is C—R³.    -   m and n are both 0; or    -   m and n are both 1;    -   L is selected from —(CH₂)_(p)—, —O—, —OCH₂— and —CH₂O—;    -   R³ is hydrogen; and    -   p is 1 or 2.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein p is 1 or 2.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein A is selected from:

-   -   (i) aryl substituted with R⁴, R⁵ and R⁶; and    -   (ii) heteroaryl substituted with R⁷, R⁸ and R⁹.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein A is selected from:

-   -   (i) phenyl substituted with R⁴, R⁵ and R⁶; and    -   (ii) oxazolyl substituted with R⁷, R⁸ and R⁹.

In another preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein A is aryl substituted with R⁴, R⁵ andR⁶.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein A is phenyl substituted with R⁴, R⁵ andR⁶.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein:

-   A is selected from:    -   (i) aryl substituted with R⁴, R⁵ and R⁶; and    -   (ii) heteroaryl substituted with R⁷, R⁸ and R⁹;-   R⁴ is selected from hydrogen, halogen, halo-C₁₋₆-alkoxy and    halo-C₁₋₆-alkyl;-   R⁵ is selected from hydrogen, cyano, halogen, C₁₋₆-alkyl,    C₁₋₆-alkoxy, heterocycloalkyl, C₃₋₁₀-cycloalkyl, heteroaryl and    haloaryl;-   R⁶ is hydrogen or halogen;-   R⁷ is selected from hydrogen, C₁₋₆-alkyl, aryl and halo-C₁₋₆-alkyl;-   R⁸ is hydrogen or C₁₋₆-alkyl; and-   R⁹ is hydrogen.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein:

-   A is selected from:    -   (i) aryl substituted with R⁴, R⁵ and R⁶; and    -   (ii) heteroaryl substituted with R⁷, R⁸ and R⁹;-   R⁴ is selected from halogen, halo-C₁₋₆-alkoxy and halo-C₁₋₆-alkyl;-   R⁵ is selected from hydrogen, cyano, halogen, heterocycloalkyl,    C₃₋₁₀-cycloalkyl and haloaryl;-   R⁶ is hydrogen;-   R⁷ is C₁₋₆-alkyl;-   R⁸ is hydrogen; and-   R⁹ is hydrogen.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein:

-   A is selected from:    -   (i) phenyl substituted with R⁴, R⁵ and R⁶; and    -   (ii) oxazolyl substituted with R⁷, R⁸ and R⁹;-   R⁴ is selected from chloro, OCF₃ and CF₃;-   R⁵ is selected from hydrogen, cyano, fluoro, chloro, pyrrolidinyl,    cyclopentyl, cyclopropyl and chlorophenyl;-   R⁶ is hydrogen;-   R⁷ is tert-butyl;-   R⁸ is hydrogen; and-   R⁹ is hydrogen.

In a further particularly preferred embodiment, the present inventionprovides a compound of formula (I) as described herein, or apharmaceutically acceptable salt thereof, wherein A is selected fromphenyl, 4-tert-butylthiazol-2-yl, 4-tert-butyloxazol-2-yl,2-chloro-4-fluoro-phenyl, 4-(trifluoromethyl)phenyl,4-(trifluoromethoxy)phenyl, 4-chlorophenyl,5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl, 3-phenyl-1,2,4-oxadiazol-5-yl,5-(trifluoromethyl)-2-pyridyl, 4-(trifluoromethyl)pyrazol-1-yl,2-fluoro-4-(trifluoromethyl)phenyl, 2,4-difluorophenyl,4-chloro-3-fluoro-phenyl, 4-cyanophenyl, 4,4-difluoro-1-piperidyl,5-tert-butyloxazol-2-yl, 4-methoxy-2-fluoro-phenyl,2-chloro-4(trifluoromethyl)phenyl, 6-(trifluoromethyl)-3-pyridyl,3-(trifluoromethyl)phenyl, 2-chloro-4-(trifluoromethoxy)phenyl,4-chloro-2-fluoro-phenyl, 4-fluoro-2-(trifluoromethyl)phenyl,2-pyrrolidin-1-yl-4-(trifluoromethyl)phenyl, 4-fluoro-2-cyano-phenyl,2-cyclopentyl-4-(trifluoromethyl)phenyl, 2-chloro-4-cyanophenyl,4-(trifluoromethyl)imidazol-1-yl, 4-fluoro-2-methyl-phenyl,4-tert-butylpyrazol-1-yl, 1,3-benzoxazol-2-yl,4-chloro-3-(4-chlorophenyl)phenyl,2-(1H-pyrazol-4-yl)-4-(trifluoromethyl)phenyl, 2,4-dichlorophenyl,3-methoxy-4-(trifluoromethyl)phenyl,5-methyl-6-(trifluoromethyl)-3-pyridyl, 3-chlorophenyl, 2-chlorophenyl,2-cyclopropyl-4-(trifluoromethyl)phenyl,2-methyl-4-(trifluoromethyl)phenyl, 3-fluoro-5-(trifluoromethyl)phenyl,2-fluoro-6-(trifluoromethyl)phenyl, 3-chloro-4-(trifluoromethyl)phenyl,2,4-difluoro-5-(trifluoromethyl)phenyl,2-fluoro-5-(trifluoromethyl)phenyl, 2-methoxy-4-(trifluoromethyl)phenyl,4-chloro-2-(trifluoromethyl)phenyl, 4-chloro-3-(trifluoromethyl)phenyl,4-chloro-3-cyclopropyl-phenyl, 4-chloro-3-morpholino-phenyl,2-cyano-4-(trifluoromethyl)phenyl, oxazolo[5,4-c]pyridin-2-yl,4-Methyl-3-(trifluoromethyl)phenyl,3-cyclopropyl-4-(trifluoromethyl)phenyl, 2-fluoro-4-methyl-phenyl,4-methoxy-2-(trifluoromethyl)phenyl, 4-methyl-2-(trifluoromethyl)phenyl,3,4-dichlorophenyl, 2,5-dichlorophenyl,5-methyl-6-(trifluoromethyl)-3-pyridyl,4,5-bis(trifluoromethyl)-2-pyridyl, 2-fluoro-4-(trifluoromethyl)-phenyl,2-fluoro-4-(pentafluoro-lambda6-sulfanyl)phenyl,2,4-bis(trifluoromethyl)phenyl, 2-methyl-3-(trifluoromethyl)phenyl,2-methyl-4-(trifluoromethoxy)phenyl, 3-chloro-4-(trifluoromethyl)phenyl,3-cyclopropyl-4-chloro-phenyl, 2-chloro-3-(trifluoromethyl)phenyl,2-chloro-3-cyclopropyl-phenyl,3-(2-azaspiro[3.3]heptan-2-yl)-4-(trifluoromethyl)phenyl,2-chloro-3-(2-azaspiro[3.3]heptan-2-yl)-phenyl,2-chloro-3-(5-oxa-2-azaspiro[3.5]nonan-2-yl)phenyl,2-fluoro-4-(trifluoromehtly)phenyl, 2-fluoro-4-methyl-phenyl,2-fluoro-6-(trifluoromethyl)phenyl, and2-(trifluoromethyl)-4-methyl-phenyl.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R¹ is hydrogen or methyl.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein R¹ is hydrogen.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R² is hydrogen or C₁₋₆-alkyl.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein R² is hydrogen or methyl.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R³ is selected from hydrogen, halogen, C₁₋₆-alkyl andhalo-C₁₋₆-alkyl.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein R³ is selected from hydrogen, halogen and C₁₋₆-alkyl.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein R³ is selected from hydrogen, fluoroand methyl.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R³ is selected from hydrogen, methyl, fluoro andtrifluoromethyl.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R⁴ is selected from hydrogen, halogen, halo-C₁₋₆-alkoxy andhalo-C₁₋₆-alkyl.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein R⁴ is selected from halogen, halo-C₁₋₆-alkoxy andhalo-C₁₋₆-alkyl.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is selected from chloro, OCF₃ andCF₃.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R⁴ is selected from hydrogen, chloro, fluoro, OCF₃ and CF₃.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R⁵ is selected from hydrogen, cyano, halogen, C₁₋₆-alkyl,C₁₋₆-alkoxy, heterocycloalkyl, C₃₋₁₀-cycloalkyl, heteroaryl andhaloaryl.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein R⁵ is selected from hydrogen, cyano, halogen,heterocycloalkyl, C₃₋₁₀-cycloalkyl and haloaryl.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is selected from hydrogen, cyano,fluoro, chloro, pyrrolidinyl, cyclopentyl, cyclopropyl and chlorophenyl.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R⁵ is selected from hydrogen, methyl, methoxy, cyano, fluoro,chloro, pyrolidinyl, morpholinyl, pyrazolyl, cyclopentyl, cyclopropyland 4-chlorophenyl.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R⁶ is hydrogen or halogen.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein R⁶ is hydrogen or fluoro.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein R⁶ is hydrogen.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R⁷ is selected from hydrogen, C₁₋₆-alkyl, aryl andhalo-C₁₋₆-alkyl.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein R⁷ is C₁₋₆-alkyl.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein R⁷ is tert-butyl.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R⁷ is selected from hydrogen, tert-butyl, phenyl and CF₃.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R⁸ is hydrogen or C₁₋₆-alkyl.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein R⁸ is hydrogen or methyl.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is hydrogen.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R⁹ is hydrogen.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R¹⁰ is halogen.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein R¹⁰ is fluoro.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R¹¹ is halogen.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein R¹¹ is fluoro.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein R¹⁰ and R¹¹ are both fluoro.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R¹² is hydrogen.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein:

-   -   (i) X is C—R³; m is 0 or 1; n is selected from 0, 1 and 2; and L        is selected from —(CH₂)_(p)—, —O—, —OCH₂—, —CH₂O— and —CH₂OCH₂—;        or    -   (ii) X is N; m and n are both 1; and L is —(CH₂)_(p)—;    -   p is 1 or 2;    -   A is selected from:        -   (i) aryl substituted with R⁴, R⁵ and R⁶;        -   (ii) heteroaryl substituted with R⁷, R⁸ and R⁹; and        -   (iii) heterocycloalkyl substituted with R¹⁰, R¹¹ and R¹²;    -   R¹ is hydrogen or C₁₋₆-alkyl;    -   R² is selected from hydrogen or C₁₋₆-alkyl;    -   R³ is selected from hydrogen, halogen, C₁₋₆-alkyl and        halo-C₁₋₆-alkyl;    -   R⁴ is selected from hydrogen, halogen, halo-C₁₋₆-alkoxy and        halo-C₁₋₆-alkyl;    -   R⁵ is selected from hydrogen, cyano, halogen, C₁₋₆-alkyl,        C₁₋₆-alkoxy, heterocycloalkyl, C₃₋₁₀-cycloalkyl, heteroaryl and        haloaryl;    -   R⁶ is hydrogen or halogen;    -   R⁷ is selected from hydrogen, C₁₋₆-alkyl, aryl and        halo-C₁₋₆-alkyl;    -   R⁸ is hydrogen or C₁₋₆-alkyl;    -   R⁹ is hydrogen;    -   R¹⁰ is halogen;    -   R¹¹ is halogen, and    -   R¹² is hydrogen.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein:

-   -   X is C—R³.    -   m and n are both 0; or    -   m and n are both 1;    -   L is selected from —(CH₂)_(p)—, —O—, —OCH₂— and —CH₂O—;    -   p is 1 or 2;    -   A is selected from:        -   (i) aryl substituted with R⁴, R⁵ and R⁶; and        -   (ii) heteroaryl substituted with R⁷, R⁸ and R⁹;    -   R¹ is hydrogen;    -   R² is selected from hydrogen or C₁₋₆-alkyl;    -   R³ is selected from hydrogen, halogen and C₁₋₆-alkyl;    -   R⁴ is selected from halogen, halo-C₁₋₆-alkoxy and        halo-C₁₋₆-alkyl;    -   R⁵ is selected from hydrogen, cyano, halogen, heterocycloalkyl,        C₃₋₁₀-cycloalkyl and haloaryl;    -   R⁶ is hydrogen;    -   R⁷ is C₁₋₆-alkyl;    -   R⁸ is hydrogen; and    -   R⁹ is hydrogen.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein:

-   -   X is C—R³    -   m and n are both 0; or    -   m and n are both 1;    -   L is selected from —(CH₂)_(p)—, —O—, —OCH₂— and —CH₂O—;    -   p is 1 or 2;    -   A is selected from:        -   (i) phenyl substituted with R⁴, R⁵ and R⁶; and        -   (ii) oxazolyl substituted with R⁷, R⁸ and R⁹;    -   R¹ is hydrogen;    -   R² is selected from hydrogen or methyl;    -   R³ is selected from hydrogen, fluoro and methyl;    -   R⁴ is selected from chloro, OCF₃ and CF₃;    -   R⁵ is selected from hydrogen, cyano, fluoro, chloro,        pyrrolidinyl, cyclopentyl, cyclopropyl and chlorophenyl;    -   R⁶ is hydrogen;    -   R⁷ is tert-butyl;    -   R⁸ is hydrogen; and    -   R⁹ is hydrogen.

In one aspect, the present invention provides a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein:

-   -   (i) X is C—R³; m is 0 or 1; n is selected from 0, 1 and 2; and L        is selected from —(CH₂)_(p)—, —O—, —OCH₂—, —CH₂OCH₂—, —CF₂CH₂—,        —CH₂═CH₂—, —(CR¹⁶R¹⁷)_(q)—CH₂O—, and —CH₂CF₂—; or    -   (ii) X is N; m is 1; n is 1 or 2; and L is —(CH₂)_(p)— or        —CF₂CH₂—;    -   p is selected from 1, 2 and 3;    -   q is 0 or 1;    -   A is selected from:        -   (i) C₆-C₁₄-aryl substituted with R⁴, R⁵ and R⁶;        -   (ii) 5- to 14-membered heteroaryl substituted with R⁷, R⁸            and R⁹; and        -   (iii) 3- to 14-membered heterocycloalkyl substituted with            R¹⁰, R¹¹ and R¹²;    -   R¹ is hydrogen or C₁₋₆-alkyl;    -   R² is selected from hydrogen, C₁₋₆-alkyl and hydroxy-C₁₋₆-alkyl;    -   R³ is selected from hydrogen, halogen, hydroxy, C₁₋₆-alkoxy,        C₁₋₆-alkyl and halo-C₁₋₆-alkyl;    -   each of R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is        independently selected from hydrogen, halogen, cyano, hydroxy,        C₁₋₆-alkyl, halo-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, C₁₋₆-alkanoyl,        halo-C₁₋₅-alkyl-CH(OH)—, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, SF₅,        CH₃SO₂, C₃₋₁₀-cycloalkyl, C₃₋₁₀-cycloalkyl substituted with R¹³,        3- to 14-membered heterocycloalkyl, 3- to 14-membered        heterocycloalkyl substituted with R¹⁴ and R¹⁵, 5- to 14-membered        heteroaryl, C₆-C₁₄-aryl, C₆-C₁₄-aryloxy, halo-C₆-C₁₄-aryl, and        halo-C₆-C₁₄-aryloxy;        -   each of R¹³, R¹⁴, and R¹⁵ is independently selected from            C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkyl, halo-C₁₋₆-alkoxy,            halogen, and hydroxy; and        -   R¹⁶ and R¹⁷, taken together with the carbon atom to which            they are attached, form a C₃₋₁₀-cycloalkyl.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein:

-   -   (i) X is C—R³; m is 0 or 1; n is selected from 0, 1 and 2; and L        is selected from —(CH₂)_(p)—, —O—, —OCH₂—, —CF₂CH₂—, —CH₂═CH₂—,        —(CR¹⁶R¹⁷)_(q)—CH₂O—, and —CH₂OCH₂—; or    -   (ii) X is N; m and n are both 1; and L is —(CH₂)_(p)—.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein p is 2.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein q is 0 or 1.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein q is 0.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein A is selected from:

-   -   (i) C₆-C₁₄-aryl substituted with R⁴, R⁵ and R⁶; and    -   (ii) 5- to 14-membered heteroaryl substituted with R⁷, R⁸ and        R⁹.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein A is selected from:

-   -   (i) phenyl substituted with R⁴, R⁵ and R⁶;    -   (ii) oxazolyl substituted with R⁷, R⁸ and R⁹; and    -   (iii) pyridyl substituted with R⁷, R⁸ and R⁹.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R⁴ is selected from hydrogen, halogen, hydroxy, cyano,C₁₋₆-alkyl, C₁₋₆-alkanoyl, SF₅, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,halo-C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 3- to 14-membered heterocyclyl, 3- to14-membered heterocycloalkyl substituted with R¹⁴ and R¹⁵, 5- to14-membered heteroaryl, C₆-C₁₄-aryloxy, and halo-C₆-C₁₄-aryl.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein R⁴ is selected from halogen, SF₅, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, halo-C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, and 3-to 14-membered heterocycloalkyl.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is selected from chloro, SF₅,methyl, methoxy, OCF₃, CF₃, cyclopropyl, and 2-azaspiro[3.3]heptan-2-yl.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R⁵ is selected from hydrogen, cyano, halogen, C₁₋₆-alkyl,halo-C₁₋₆-alkyl, C₁₋₆-alkoxy, 3- to 14-membered heterocycloalkyl,C₃₋₁₀-cycloalkyl, 5- to 14-membered heteroaryl. and halo-C₆-C₁₄-aryl.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein R⁵ is selected from hydrogen, cyano, halogen,C₁₋₆-alkyl, halo-C₁₋₆-alkyl, 3- to 14-membered heterocycloalkyl,C₃₋₁₀-cycloalkyl and halo-C₆-C₁₄-aryl.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is selected from hydrogen, cyano,fluoro, chloro, methyl, CF₃, pyrrolidinyl, cyclopentyl, cyclopropyl andchlorophenyl.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R⁷ is selected from hydrogen, C₁₋₆-alkyl, C₆-C₁₄-aryl,halo-C₆-C₁₄-aryl, halo-C₆-C₁₄-aryloxy, and halo-C₁₋₆-alkyl.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein R⁷ is C₁₋₆-alkyl or halo-C₁₋₆-alkyl.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein R⁷ is tert-butyl or CF₃.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R⁸ is selected from hydrogen, halogen, C₁₋₆-alkyl, andhalo-C₁₋₆-alkyl.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein R⁸ is hydrogen or halo-C₁₋₆-alkyl.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is hydrogen or CF₃.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R¹⁴ is selected from C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein R¹⁵ is hydrogen or halogen.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein:

-   -   (i) X is C—R³; m is 0 or 1; n is selected from 0, 1 and 2; and L        is selected from —(CH₂)_(p)—, —O—, —OCH₂—, —(CR¹⁶R¹⁷)_(q)—CH₂O—,        —CH₂OCH₂—, —CF₂CH₂—, and —CH₂═CH₂—; or    -   (ii) X is N; m and n are both 1; and L is —(CH₂)_(p)—;    -   p is 1 or 2;    -   q is 0 or 1;    -   A is selected from:        -   (i) C₆-C₁₄-aryl substituted with R⁴, R⁵ and R⁶;        -   (ii) 5- to 14-membered heteroaryl substituted with R⁷, R⁸            and R⁹; and        -   (iii) 3- to 14-membered heterocycloalkyl substituted with            R¹⁰, R¹¹ and R¹²;    -   R¹ is hydrogen or C₁₋₆-alkyl;    -   R² is hydrogen or C₁₋₆-alkyl;    -   R³ is selected from hydrogen, halogen, C₁₋₆-alkyl and        halo-C₁₋₆-alkyl;    -   R⁴ is selected from hydrogen, halogen, cyano, SF₅, C₁₋₆-alkyl,        C₁₋₆-alkanoyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, halo-C₁₋₆-alkyl,        C₃₋₁₀-cycloalkyl, 3- to 14-membered heterocycloalkyl, 3- to        14-membered heterocycloalkyl substituted with R¹⁴ and R¹⁵, 5- to        14-membered heteroaryl, halo-C₆-C₁₄-aryl, and C₆-C₁₄-aryloxy;    -   R⁵ is selected from hydrogen, cyano, halogen, C₁₋₆-alkyl,        halo-C₁₋₆-alkyl, C₁₋₆-alkoxy, 3- to 14-membered        heterocycloalkyl, C₃₋₁₀-cycloalkyl, 5- to 14-membered heteroaryl        and halo-C₆-C₁₄-aryl;    -   R⁶ is hydrogen or halogen;    -   R⁷ is selected from hydrogen, C₁₋₆-alkyl, C₆-C₁₄-aryl,        halo-C₆-C₁₄-aryl, halo-C₆-C₁₄-aryloxy, and halo-C₁₋₆-alkyl;    -   R⁸ is selected from hydrogen, halogen, C₁₋₆-alkyl, and        halo-C₁₋₆-alkyl;    -   R⁹ is hydrogen;    -   R¹⁰ is halogen;    -   R¹¹ is halogen;    -   R¹² is hydrogen;    -   R¹⁴ is selected from halogen, C₁₋₆-alkyl, and C₁₋₆-alkoxy;    -   R¹⁵ is hydrogen or halogen; and    -   R¹⁶ and R¹⁷, taken together with the carbon atom to which they        are attached, form a C₃₋₁₀-cycloalkyl.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein:

-   -   X is C—R³.    -   m and n are both 0; or    -   m and n are both 1;    -   L is selected from —(CH₂)_(p)—, —O—, —OCH₂— and —CH₂O—;    -   p is 1 or 2;    -   A is selected from:        -   (i) C₆-C₁₄-aryl substituted with R⁴, R⁵ and R⁶; and        -   (ii) 5- to 14-membered heteroaryl substituted with R⁷, R⁸            and R⁹;    -   R¹ is hydrogen;    -   R² is hydrogen or C₁₋₆-alkyl;    -   R³ is selected from hydrogen, halogen and C₁₋₆-alkyl;    -   R⁴ is selected from halogen, SF₅, C₁₋₆-alkyl, C₁₋₆-alkoxy,        halo-C₁₋₆-alkoxy, halo-C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, and 3- to        14-membered heterocycloalkyl;    -   R⁵ is selected from hydrogen, cyano, halogen, C₁₋₆-alkyl,        halo-C₁₋₆-alkyl, 3- to 14-membered heterocycloalkyl,        C₃₋₁₀-cycloalkyl and halo-C₆-C₁₄-aryl;    -   R⁶ is hydrogen;    -   R⁷ is C₁₋₆-alkyl or halo-C₁₋₆-alkyl;    -   R⁸ is hydrogen or halo-C₁₋₆-alkyl; and    -   R⁹ is hydrogen.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein:

-   -   X is C—R³    -   m and n are both 0; or    -   m and n are both 1;    -   L is selected from —(CH₂)_(p)—, —O—, —OCH₂— and —CH₂O—;    -   p is 1 or 2;    -   A is selected from:        -   (i) phenyl substituted with R⁴, R⁵ and R⁶;        -   (ii) oxazolyl substituted with R⁷, R⁸ and R⁹; and        -   (iii) pyridyl substituted with R⁷, R⁸ and R⁹;    -   R¹ is hydrogen;    -   R² is hydrogen or methyl;    -   R³ is selected from hydrogen, fluoro and methyl;    -   R⁴ is selected from chloro, SF₅, methyl, methoxy, OCF₃, CF₃,        cyclopropyl, and 2-azaspiro[3.3]heptan-2-yl;    -   R⁵ is selected from hydrogen, cyano, fluoro, chloro, methyl,        CF₃, pyrrolidinyl, cyclopentyl, cyclopropyl and chlorophenyl;    -   R⁶ is hydrogen;    -   R⁷ is selected from tert-butyl, methyl, and CF₃;    -   R⁸ is hydrogen or CF₃; and    -   R⁹ is hydrogen.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein:

-   -   X is C—R³; and    -   R³ is selected from hydrogen, halogen and C₁₋₆-alkyl.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein:

-   -   X is C—R³; and    -   R³ is selected from hydrogen, fluoro and methyl.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein:

-   -   (i) X is C—R³; m is 0 or 1; n is selected from 0, 1 and 2; and L        is selected from —(CH₂)_(p)—, —O—, —OCH₂—, —(CR¹⁶R¹⁷)_(q)—CH₂O—,        —CH₂OCH₂—, —CF₂CH₂—, and —CH₂═CH₂—; or    -   (ii) X is N; m and n are both 1; and L is —(CH₂)_(p)—;    -   p is 1 or 2;    -   q is 0 or 1;    -   R³ is selected from hydrogen, halogen and C₁₋₆-alkyl; and    -   R¹⁶ and R¹⁷, taken together with the carbon atom to which they        are attached, form a C₃₋₁₀-cycloalkyl.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein:

-   -   X is C—R³.    -   m and n are both 0; or    -   m and n are both 1;    -   L is selected from —(CH₂)_(p)—, —O—, —OCH₂— and —CH₂O—;    -   p is 1 or 2; and    -   R³ is selected from hydrogen, halogen and C₁₋₆-alkyl.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein:

-   -   X is C—R³    -   m and n are both 0; or    -   m and n are both 1;    -   L is selected from —(CH₂)_(p)—, —O—, —OCH₂— and —CH₂O—;    -   p is 1 or 2; and    -   R³ is selected from hydrogen, fluoro and methyl.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,wherein:

-   -   A is selected from:        -   (i) C₆-C₁₄-aryl substituted with R⁴, R⁵ and R⁶;        -   (ii) 5- to 14-membered heteroaryl substituted with R⁷, R⁸            and R⁹; and        -   (iii) 3- to 14-membered heterocycloalkyl substituted with            R¹⁰, R¹¹ and R¹²;    -   R⁴ is selected from hydrogen, halogen, cyano, SF₅, C₁₋₆-alkyl,        C₁₋₆-alkanoyl, C₁₋₆-alkoxy, halo-C_(1I)6-alkoxy,        halo-C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 3- to 14-membered        heterocycloalkyl, 3- to 14-membered heterocycloalkyl substituted        with R¹⁴ and    -   R¹⁵, 5- to 14-membered heteroaryl, halo-C₆-C₁₄-aryl, and        C₆-C₁₄-aryloxy;    -   R⁵ is selected from hydrogen, cyano, halogen, C₁₋₆-alkyl,        halo-C₁₋₆-alkyl, C₁₋₆-alkoxy, 3- to 14-membered        heterocycloalkyl, C₃₋₁₀-cycloalkyl, 5- to 14-membered heteroaryl        and halo-C₆-C₁₄-aryl;    -   R⁶ is hydrogen or halogen;    -   R⁷ is selected from hydrogen, C₁₋₆-alkyl, C₆-C₁₄-aryl,        halo-C₆-C₁₄-aryl, halo-C₆-C₁₄-aryloxy, and halo-C₁₋₆-alkyl;    -   R⁸ is selected from hydrogen, halogen, C₁₋₆-alkyl, and        halo-C₁₋₆-alkyl;    -   R⁹ is hydrogen;    -   R¹⁰ is halogen;    -   R¹¹ is halogen;    -   R¹² is hydrogen;    -   R¹⁴ is selected from halogen, C₁₋₆-alkyl, and C₁₋₆-alkoxy; and    -   R¹⁵ is hydrogen or halogen.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein:

-   -   A is selected from:        -   (i) C₆-C₁₄-aryl substituted with R⁴, R⁵ and R⁶; and        -   (ii) 5- to 14-membered heteroaryl substituted with R⁷, R⁸            and R⁹;    -   R⁴ is selected from halogen, SF₅, C₁₋₆-alkyl, C₁₋₆-alkoxy,        halo-C₁₋₆-alkoxy, halo-C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, and 3- to        14-membered heterocycloalkyl;    -   R⁵ is selected from hydrogen, cyano, halogen, C₁₋₆-alkyl,        halo-C₁₋₆-alkyl, 3- to 14-membered heterocycloalkyl,        C₃₋₁₀-cycloalkyl and halo-C₆-C₁₄-aryl;    -   R⁶ is hydrogen;    -   R⁷ is C₁₋₆-alkyl or halo-C₁₋₆-alkyl;    -   R⁸ is hydrogen or halo-C₁₋₆-alkyl; and    -   R⁹ is hydrogen.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein:

-   -   A is selected from:        -   (i) phenyl substituted with R⁴, R⁵ and R⁶;        -   (ii) oxazolyl substituted with R⁷, R⁸ and R⁹; and        -   (iii) pyridyl substituted with R⁷, R⁸ and R⁹;    -   R⁴ is selected from chloro, SF₅, methyl, methoxy, OCF₃, CF₃,        cyclopropyl, and 2-azaspiro[3.3]heptan-2-yl;    -   R⁵ is selected from hydrogen, cyano, fluoro, chloro, methyl,        CF₃, pyrrolidinyl, cyclopentyl, cyclopropyl and chlorophenyl;    -   R⁶ is hydrogen;    -   R⁷ is tert-butyl, methyl, and CF₃;    -   R⁸ is hydrogen or CF₃; and    -   R⁹ is hydrogen.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein:

-   -   X is C—H;    -   m and n are both 0;    -   L is —CH₂O—;    -   A is C₆-C₁₄-aryl substituted with R⁴, R⁵ and R⁶;    -   R¹, R², and R⁶ are all hydrogen;    -   R⁴ is halo-C₁₋₆-alkyl; and    -   R⁵ is halogen or C₁₋₆-alkyl.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein:

-   -   X is C—H;    -   m and n are both 0;    -   L is —CH₂O—;    -   A is C₆-C₁₄-aryl substituted with R⁴, R⁵ and R⁶;    -   R¹, R², and R⁶ are all hydrogen;    -   R⁴ is halo-C₁₋₆-alkyl; and    -   R⁵ is halogen.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, wherein:

-   -   X is C—H;    -   m and n are both 0;    -   L is —CH₂O—;    -   A is phenyl substituted with R⁴, R⁵ and R⁶;    -   R¹, R², and R⁶ are all hydrogen;    -   R⁴ is CF₃; and    -   R⁵ is fluoro or methyl.

In a particularly preferred embodiment, the present invention provides acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, wherein:

-   -   X is C—H;    -   m and n are both 0;    -   L is —CH₂O—;    -   A is phenyl substituted with R⁴, R⁵ and R⁶;    -   R¹, R², and R⁶ are all hydrogen;    -   R⁴ is CF₃; and    -   R⁵ is fluoro.

In one embodiment, the present invention provides a compound of formula(I) as described herein, or a pharmaceutically acceptable salt thereof,selected from the compounds disclosed in Table 1.

In a preferred embodiment, the present invention provides a compound offormula (I) as described herein, or a pharmaceutically acceptable saltthereof, selected from:

-   (+)-(4aR,8aS)-6-(4-((4-(tert-Butyl)oxazol-2-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)-(4aR,8aS)-6-[4-[[4-(Trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (+)-(4aR,8aS)-6-(4-((2-Chloro-4-fluorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   rac-(4aR,8aS)-6-(3-((2-Fluoro-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(3-((2-Chloro-4-fluorobenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(3-((2-Fluoro-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(4-(4-(Trifluoromethoxy)benzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(4-(4-Chloro-3-fluorobenzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(4-(2-Chloro-4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(4-(3-(Trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-[4-[[2-Chloro-4-(trifluoromethoxy)phenoxy]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (+)- or    (−)-(4aR,8aS)-6-(3-((2-Fluoro-4-(trifluoromethyl)phenoxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(4-((4-Chloro-2-fluorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(4-((4-Fluoro-2-(trifluoromethyl)phenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(4-((2-Fluoro-4-(trifluoromethyl)phenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(4-(2-(Pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(4-((2-Chloro-4-(trifluoromethyl)phenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-[4-[[2-Cyclopentyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (+)- or    (−)-3-Chloro-4-((1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-yl)methoxy)benzonitrile;-   (+)- or    (−)-(4aR,8aS)-6-(3-((2-Chloro-4-(trifluoromethyl)phenoxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(4-((2-Chloro-4-fluorophenoxy)methyl)-4-fluoropiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(4-((4′,6-Dichloro-[1,1′-biphenyl]-3-yl)oxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(cis-4-((2-Chloro-4-fluorophenoxy)methyl)-3-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(3-((2-Chloro-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(3-((2-Fluoro-4-(trifluoromethoxy)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (+)- or    (−)-(4aR,8aS)-6-(4-((2-Chloro-4-fluorophenoxy)methyl)-4-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (4aR,8aS)-6-[3-[(2,4-Dichlorophenyl)methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-[4-[[2-Fluoro-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-[4-[[2-Cyclopropyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-[3-[[3-Chloro-4-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-[3-[[2-Fluoro-5-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-[3-[2-[2-Fluoro-6-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-(3-(2-fluoro-4-(trifluoromethyl)phenethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   6-(3-((2,4-bis(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (4aR,8aS)-6-[4-[3-chloro-4-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-(3-methyl-4-(((5-methyl-6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (4aR,8aS)-6-(3-((3,4-dichlorobenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (4aR,8aS)-6-(3-((2,5-dichlorobenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   rac-(4aR,8aS)-6-(2-methyl-3-((4-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (4aR,8aS)-6-(3-(((4,5-bis(trifluoromethyl)pyridin-2-yl)oxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   rac-(4aR,8aS)-6-(3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)-2-methylazetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (4aR,8aS)-6-(3-((2-fluoro-4-(pentafluoro-16-sulfaneyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (4aR,8aS)-6-(3-((4-methyl-2-(trifluoromethoxy)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (4aR,8aS)-6-[4-[3-cyclopropyl-4-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-[3-[2-(2-fluoro-4-methyl-phenyl)ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-[3-[2-[4-methoxy-2-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-[3-[3-(2-azaspiro[3.3]heptan-2-yl)-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-[3-[2-[4-methyl-2-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-(3-((4-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   (4aR,8aS)-6-(3-((2-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;-   rac-(4aR,8aS)-6-[2-methyl-3-[[2-methyl-4-(trifluoromethoxy)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   rac-(4aR,8aS)-6-[2-methyl-3-[[2-methyl-3-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-[3-(4-chloro-3-cyclopropylphenoxy)azetidine-1-carbonyl]-4,4#a!,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-[4-[2-chloro-3-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-[3-(2-chloro-3-cyclopropyl-phenoxy)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-[3-[3-(2-azaspiro[3.3]heptan-2-yl)-2-chloro-phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-[3-[2-chloro-3-(5-oxa-2-azaspiro[3.5]nonan-2-yl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-[3-[(E)-2-(2-fluoro-4-methyl-phenyl)vinyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;-   (4aR,8aS)-6-(3-((E)-2-fluoro-6-(trifluoromethyl)styryl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;    and-   (4aR,8aS)-6-(3-((4-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one.

In one embodiment, the present invention provides pharmaceuticallyacceptable salts or esters of the compounds of formula (I) as describedherein. In a particular embodiment, the present invention providespharmaceutically acceptable salts of the compounds according to formula(I) as described herein, especially hydrochloride salts. In a furtherparticular embodiment, the present invention provides pharmaceuticallyacceptable esters of the compounds according to formula (I) as describedherein. In yet a further particular embodiment, the present inventionprovides compounds according to formula (I) as described herein.

In some embodiments, the compounds of formula (I) areisotopically-labeled by having one or more atoms therein replaced by anatom having a different atomic mass or mass number. Suchisotopically-labeled (i.e., radiolabeled) compounds of formula (I) areconsidered to be within the scope of this disclosure. Examples ofisotopes that can be incorporated into the compounds of formula (I)include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine, chlorine, and iodine, such as, but not limited to, ²H,³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²p, ³⁵S, ¹⁸F, ³⁶Cl,¹²³I, and ¹²⁵I, respectively. Certain isotopically-labeled compounds offormula (I), for example, those incorporating a radioactive isotope, areuseful in drug and/or substrate tissue distribution studies. Theradioactive isotopes tritium, i.e. ³H, and carbon-14, i.e., ¹⁴C, areparticularly useful for this purpose in view of their ease ofincorporation and ready means of detection. For example, a compound offormula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99percent of a given isotope.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof formula (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Examples as set out below using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

Processes of Manufacturing

The preparation of compounds of formula (I) of the present invention maybe carried out in sequential or convergent synthetic routes. Synthesesof the invention are shown in the following general schemes. The skillsrequired for carrying out the reaction and purification of the resultingproducts are known to those persons skilled in the art. The substituentsand indices used in the following description of the processes have thesignificance given herein, unless indicated to the contrary.

If one of the starting materials, intermediates or compounds of formula(I) contain one or more functional groups which are not stable or arereactive under the reaction conditions of one or more reaction steps,appropriate protective groups (as described e.g., in “Protective Groupsin Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014,John Wiley & Sons, N.Y.) can be introduced before the critical stepapplying methods well known in the art. Such protective groups can beremoved at a later stage of the synthesis using standard methodsdescribed in the literature.

If starting materials or intermediates contain stereogenic centers,compounds of formula (I) can be obtained as mixtures of diastereomers orenantiomers, which can be separated by methods well known in the arte.g., chiral HPLC, chiral SFC or chiral crystallization. Racemiccompounds can e.g., be separated into their antipodes via diastereomericsalts by crystallization with optically pure acids or by separation ofthe antipodes by specific chromatographic methods using either a chiraladsorbent or a chiral eluent. It is equally possible to separatestarting materials and intermediates containing stereogenic centers toafford diastereomerically/enantiomerically enriched starting materialsand intermediates. Using such diastereomerically/enantiomericallyenriched starting materials and intermediates in the synthesis ofcompounds of formula (I) will typically lead to the respectivediastereomerically/enantiomerically enriched compounds of formula (I).

A person skilled in the art will acknowledge that in the synthesis ofcompounds of formula (I) —insofar not desired otherwise—an “orthogonalprotection group strategy” will be applied, allowing the cleavage ofseveral protective groups one at a time each without affecting otherprotective groups in the molecule. The principle of orthogonalprotection is well known in the art and has also been described inliterature (e.g. Barany and R. B. Merrifield, J. Am. Chem. Soc. 1977,99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35,2056).

A person skilled in the art will acknowledge that the sequence ofreactions may be varied depending on reactivity and nature of theintermediates.

In more detail, the compounds of formula (I) can be manufactured by themethods given below, by the methods given in the examples or byanalogous methods. Appropriate reaction conditions for the individualreaction steps are known to a person skilled in the art. Also, forreaction conditions described in literature affecting the describedreactions see for example: Comprehensive Organic Transformations: AGuide to Functional Group Preparations, 2nd Edition, Richard C. Larock.John Wiley & Sons, New York, N.Y. 1999). It was found convenient tocarry out the reactions in the presence or absence of a solvent. Thereis no particular restriction on the nature of the solvent to beemployed, provided that it has no adverse effect on the reaction or thereagents involved and that it can dissolve the reagents, at least tosome extent. The described reactions can take place over a wide range oftemperatures, and the precise reaction temperature is not critical tothe invention. It is convenient to carry out the described reactions ina temperature range between −78° C. to reflux. The time required for thereaction may also vary widely, depending on many factors, notably thereaction temperature and the nature of the reagents. However, a periodof from 0.5 hours to several days will usually suffice to yield thedescribed intermediates and compounds. The reaction sequence is notlimited to the one displayed in the schemes, however, depending on thestarting materials and their respective reactivity, the sequence ofreaction steps can be freely altered.

If starting materials or intermediates are not commercially available ortheir synthesis not described in literature, they can be prepared inanalogy to existing procedures for close analogues or as outlined in theexperimental section.

The following abbreviations are used in the present text:

AcOH=acetic acid, ACN=acetonitrile, Bn=benzyl,Boc=tert-butyloxycarbonyl, CAS RN=chemical abstracts registrationnumber, Cbz=benzyloxycarbonyl, Cs₂CO₃=cesium carbonate, CO=carbonmonoxide, CuCl=copper(I) chloride, CuCN=copper(I) cyanide, CuI=copper(I)iodide, DAST=(diethylamino)sulfur trifluoride,DBU=1,8-diazabicyclo[5,4,0]undec-7-ene, DCM=dichloromethane,DEAD=diethyl azodicarboxylate, DIAD=diisopropyl azodicarboxylate,DMAP=4-dimethylaminopyridine, DME=dimethoxyethane,DMEDA=N,N′-dimethylethylenediamine, DMF=N,N-dimethylformamide,DIPEA=N,N-diisopropylethylamine, dppf=1,1 bis(diphenylphosphino)ferrocene,EDC.HCl=N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride,EI=electron impact, ESI=electrospray ionization, EtOAc=ethyl acetate,EtOH=ethanol, h=hour(s), FA=formic acid, H₂O=water, H₂SO₄=sulfuric acid,HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate,HBTU=O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate,HCl=hydrogen chloride, HOBt=1-hydroxy-1H-benzotriazole; HPLC=highperformance liquid chromatography, iPrMgCl=isopropylmagnesium chloride,I₂=iodine, IPA=2-propanol, ISP=ion spray positive (mode), ISN=ion spraynegative (mode), K₂CO₃=potassium carbonate, KHCO₃=potassium bicarbonate,KI=potassium iodide, KOH=potassium hydroxide, K₃PO₄=potassium phosphatetribasic, LiAlH₄ or LAH=lithium aluminium hydride, LiHMDS=lithiumbis(trimethylsilyl)amide, LiOH=lithium hydroxide, MgSO₄=magnesiumsulfate, min=minute(s), mL=milliliter, MPLC=medium pressure liquidchromatography, MS=mass spectrum, nBuLi=n-butyllithium, NaBH₃CN=sodiumcyanoborohydride, NaH=sodium hydride, NaHCO₃=sodium hydrogen carbonate,NaNO₂=sodium nitrite, NaBH(OAc)₃=sodium triacetoxyborohydride,NaOH=sodium hydroxide, Na₂CO₃=sodium carbonate, Na₂SO₄=sodium sulfate,Na₂S₂O₃=sodium thiosulfate, NBS=N-bromosuccinimide,nBuLi=n-butyllithium, NEt₃=triethylamine (TEA), NH₄Cl=ammonium chloride,NMP=N-methyl-2-pyrrolidone, OAc=Acetoxy, T₃P=propylphosphonic anhydride,PE=petroleum ether, PG=protective group, Pd—C=palladium on activatedcarbon,PdCl₂(dppf)-CH₂Cl₂=1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex,Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium(0),Pd(OAc)₂=palladium(II) acetate, Pd(OH)₂=palladium hydroxide,Pd(PPh₃)₄=tetrakis(triphenylphosphine)palladium(0),PTSA=p-toluenesulfonic acid, R=any group, RT=room temperature,SFC=Supercritical Fluid Chromatography,S-PHOS=2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, TBAI=tetra butylammonium iodine, TEA=triethylamine, TFA=trifluoroacetic acid,THF=tetrahydrofuran, TMEDA=N,N,N′,N′-tetramethylethylenediamine,ZnCl₂=zinc chloride, Hal=halogen.

Compounds of formula I wherein A, L, X, m, n, R¹ and R² are as describedherein can be synthesized in analogy to literature procedures and/or asdepicted for example in Scheme 1.

Accordingly, 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-ones1 are reacted with intermediates 2 in the presence of a urea formingreagent, such as bis(trichloromethyl) carbonate using a suitable baseand solvent such as, e.g. sodium bicarbonate in DCM, to give compoundsof formula I (step a). Further urea forming reagents include but are notlimited to phosgene, trichloromethyl chloroformate,(4-nitrophenyl)carbonate or 1,1′-carbonyldiimidazole. Reactions of thistype and the use of these reagents are widely described in literature(e.g. G. Sartori et al., Green Chemistry 2000, 2, 140). A person skilledin the art will acknowledge that the order of the addition of thereagents can be important in this type of reactions due to thereactivity and stability of the intermediary formed carbamoyl chlorides,as well as for avoiding formation of undesired symmetrical ureaby-products.

Intermediates 1 may be synthesized as depicted for example in Scheme 2and/or in analogy to methods described in literature.

Thus, 3-aminopiperidin-4-ol derivatives 3 in which “PG” signifies asuitable protective group such as a Cbz or Boc protective group can beacylated for example with acyl chlorides 4 in which R¹ is as definedherein and “LG” signifies a suitable leaving group (e.g., Cl or Br),using a suitable base such as sodium or potassium carbonate, sodiumhydroxide or sodium acetate in an appropriate solvent such as THF,water, acetone or mixtures thereof, to provide intermediates 5 (step a).Intermediates 4 are either commercially available or can be preparedaccording to literature methods in achiral (R¹=H), racemic (R¹ not H) orenantiomerically pure form (R¹ not H).

Intermediates 5 can be cyclized to intermediates 6 using methods wellknown in the art, for example by treatment of 5 with sodium hydride inTHF or potassium tert-butoxide in IPA and water (step b). Reactions ofthat type are described in literature (e.g. Z. Rafinski et al., J. Org.Chem. 2015, 80, 7468; S. Dugar et al., Synthesis 2015, 47(5), 712;WO2005/066187).

Removal of the protective group in intermediates 6, applying methodsknown in the art (e.g., a Boc group using TFA in DCM at temperaturesbetween 0° C. and room temperature, a Cbz group using hydrogen in thepresence of a suitable catalyst such as Pd or Pd(OH)₂ on charcoal in asuitable solvent such as MeOH, EtOH, EtOAc or mixtures thereof and asdescribed for example in “Protective Groups in Organic Chemistry” by T.W. Greene and P. G. M. Wuts, 4th Ed., 2006, Wiley N.Y.), furnishesintermediates 1 (step c).

Intermediates 1 can be obtained as mixtures of diastereomers andenantiomers, respectively, or as single stereoisomers depending onwhether racemic mixtures or enantiomerically pure forms of cis- ortrans-3-aminopiperidin-4-ol derivatives 3 or intermediates 4 areemployed in their syntheses. Intermediates 3 are commercially availableand their synthesis has also been described in literature (e.g.WO2005/066187; WO2011/0059118; WO2016/185279). Optically purecis-configured intermediates 1B and 1C can be obtained for exampleaccording to Scheme 3 by chiral separation of commercially availablerac-(4aR,8aS)-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one(1A) (optionally in form of a salt such as, e.g. a hydrochloride salt)using methods known in the art, e.g. by diastereomeric saltcrystallization or by chiral chromatography (step a).

In some embodiments, intermediates 2 are intermediates of type B.Intermediates of type B in which A, m, n and R² are as described hereincan be prepared by methods well known by a person skilled in the art andas exemplified by the general synthetic procedures outlined in Scheme 4.

Ketones 7, either commercially available or prepared by methods known inthe art, can be subjected for example to a Wittig reaction withalkylidene triphenylphosphoranes of type 8a in a suitable solvent suchas, e.g. THF, Methyl-THF or DMSO to give intermediates 9 (step a).Phosphoranes 8a can be formed by treating the corresponding phosphoniumsalts with a suitable base such as BuLi, NaH, or KOtBu in a suitablesolvent such as THF, dioxane or Methyl-THF and may be isolated or usedin situ. Phosphonium salts in turn are readily available from anaryl/heteroaryl/heterocyclic-substituted alkylhalide (with halide beingCl, Br and iodo) and triphenylphosphine in a suitable solvent such astoluene. Heating may be applied to accelerate the reaction or drive thereaction to completion (e.g. H. J. Cristau, F. Plénat in PATAI'SChemistry of Functional Groups, Editor(s): Frank R. Hartley, 7 Aug.2006, Series Editor(s): Prof Saul Patai).

Alternatively, intermediates 9 can be obtained using aHorner-Wadsworth-Emmons (HWE) reaction using ketones 7 and phosphonates8b, wherein R^(a) is alkyl, for example methyl or ethyl. Phosphonates 8bare in situ α-metalated using a suitable base and solvent such as NaH,nBuLi or KOtBu in THF (step a). Phosphonates 8b are readily preparedusing for example the Arbuzov reaction by alkylation of anaryl/heteroaryl/heterocyclic halide (with halide being Cl, Br and iodo)with commercially available trialkyl phosphite (e.g. Chem. Rev. 1984,84, 577).

Olefination reactions of both types are broadly described in literature(e.g. Current Org. Chem. 2015, 19(9), page 744; Chem. Rev. 1989, 89(4),863; Org. React. 1977, 25, 73; Liebigs Ann. Recueil 1997, 1283; Acc.Chem. Res. 1983, 16, 411).

Reduction of the double bond in intermediates 9 using, e.g. hydrogen inthe presence of a suitable catalyst such as palladium on charcoal in anappropriate solvent or solvent mixture such as EtOAc, MeOH or AcOHyields compounds 10 (step b).

Removal of the protective group from intermediates 10 applying methodsknown in the art (e.g., a Boc group using TFA in DCM or 4M HCl indioxane at temperatures between 0° C. and room temperature, a Cbz groupusing hydrogen in the presence of a suitable catalyst such as Pd orPd(OH)₂ on charcoal in a suitable solvent such as MeOH, EtOH, EtOAc ormixtures thereof and as described for example in “Protective Groups inOrganic Chemistry” by T. W. Greene and P. G. M. Wuts, 4th Ed., 2006,Wiley N.Y.), furnishes intermediates B (step c).

In some embodiments, intermediates 2 are intermediates of type C.Intermediates of type C in which A, R² and p are as described herein,r=0, 1 or 2 and (m+n)=2 or 3 can be prepared by methods well known inthe art and as exemplified by the general synthetic procedures outlinedin Scheme 5.

Alkylation of optionally mono-protected piperazine or 1,4-diazepanederivatives 11a,b (commercially available or synthesized in analogy toliterature methods) with aryl/heteroaryl/heterocyclyl-substituted alkylderivatives 12, either commercially available or synthesized accordingto literature procedures and in which LG signifies a suitable leavinggroup such as chlorine, bromine, iodine, OSO₂alkyl (e.g. mesylate(methanesulfonate), OSO₂fluoroalkyl (e.g. triflate(trifluoromethanesulfonate) or OSO₂aryl (e.g. tosylate(p-toluenesulfonate using a suitable base in an appropriate solvent(e.g. sodium hydride in DMF) at temperatures between 0° C. and theboiling temperature of the solvent, gives intermediates 14a,b (step a).

Alternatively, compounds 11a,b can be subjected to a reductive aminationreaction with aldehydes of type 13 using a suitable reducing agent andsolvent such as NaBH₃CN in MeOH, AcOH or mixtures thereof to giveintermediates 14a,b (step a).

Removal of the protective group from intermediates 14b applying methodsknown in the art (e.g., a Boc group using TFA in DCM or 4M HCl indioxane at temperatures between 0° C. and room temperature, a Cbz groupusing hydrogen in the presence of a suitable catalyst such as Pd orPd(OH)₂ on charcoal in a suitable solvent such as MeOH, EtOH, EtOAc ormixtures thereof and as described for example in “Protective Groups inOrganic Chemistry” by T. W. Greene and P. G. M. Wuts, 4th Ed., 2006,Wiley N.Y.), furnishes intermediates C (step c).

In some embodiments, compounds of formula I are compounds of type Ie.Compounds Ie in which A, p, R¹ and R² are defined as herein and (m+n)=2or 3 can be prepared in analogy to literature procedures or the methodsdescribed under Scheme 6 below.

Compounds 1 can be coupled with piperazine or 1,4-diazepane derivatives11a applying for example the conditions outlined under Scheme 1, step a,to give intermediates 15 (step a).

Intermediates 15 can be converted to compounds IC in analogy to theprocedure described under Scheme 5, step a (step b).

Alternatively, compounds 1 can be coupled with mono-protected piperazineor 1,4-diazepane derivatives 11b in which PG signifies a suitableprotective group such as a Cbz or Boc protective group applying forexample the conditions outlined under Scheme 1, step a, to giveintermediates 16 (step c).

Removal of the protective group by published methods or as describedunder Scheme 5, step c, furnishes intermediates 15 (step d).

In some embodiments, intermediates 2 are intermediates of type D.Intermediates of type D in which A, m, n and R² are as described hereinand R³ is selected from hydrogen, halogen, C₁₋₆-alkoxy, C₁₋₆-alkyl andhalo-C₁₋₆-alkyl, can be prepared by methods well known in the art and asexemplified by the general synthetic procedures outlined in Scheme 7.

Alcohols of type 17 can be subjected to a Mitsunobu reaction withintermediates 18 in which PG is a suitable protective group such as aCbz, Boc or Bn, using an appropriate phosphine such astriphenylphosphine and a dialkyl azodicarboxylate such as DEAD or DIADin a suitable solvent such as THF to give intermediates 19 (step a).Mitsunobu reactions of that type are broadly described in literature(e.g. Org. Chem. Front. 2015, 2, 739; Chem. Rev. 2009, 109 (6), 2551).

Removal of the protective group from intermediates 19 applyingliterature methods and as described for example under Scheme 3, step c,furnishes intermediates D (step b).

Alternatively, intermediates 19 may be prepared from alcohols 17 thatcan be alkylated with compounds 20 in which LG is a suitable leavinggroup such as chlorine, bromine, iodine, OSO₂alkyl (e.g.methanesulfonate), OSO₂fluoroalkyl (e.g. trifluoromethanesulfonate) orOSO₂aryl (e.g. p-toluenesulfonate using a suitable base in anappropriate solvent (e.g. sodium hydride in DMF) at temperatures between0° C. and the boiling temperature of the solvent (step c).

Furthermore, intermediates 19 may be synthesized via alkylation ofalcohols of type 18 with compounds 21 under the conditions describedunder step c (step d).

In another embodiment, intermediates 2 are intermediates of type E.Intermediates of type E in which A, m, n, R² and R³ are as describedherein, can be prepared by methods well known in the art and asexemplified by the general synthetic procedures outlined in Scheme 8. Incase R³ is a hydroxy group a suitable protective group strategy known tothose skilled in the art may be applied.

The carboxylic acid functionality in derivatives 22 in which PGsignifies a suitable protecting group such as, e.g. a Boc, Cbz or Bnprotecting group, either commercially available or prepared by methodsknown in the art, can be converted into an acid chloride (LG=Cl) orWeinreb amide (LG=NMeOMe) by applying methods broadly described inliterature to give intermediates 23 (step a).

Intermediates 23 can be reacted with compounds of type 24, eithercommercially available or synthesized by methods known in the art and asdescribed below to yield intermediates 25 (step b).

If compounds 24 are commercially not available they can be prepared inanalogy to literature methods. For example, deprotonation of a reactivemethyl group in optionally substituted heterocycles 27 using anappropriate base such nBuLi or LiHMDS in a suitable solvent, e.g. THF,hexane or mixtures thereof, at temperatures ranging from −78° C. to roomtemperature, gives intermediates 24 in which MX=Li (step d).

Compounds 24 in which MX=MgHal with Hal being Cl, Br or I (Grignardreagents) may be prepared by reaction of the corresponding substitutedbenzyl halides 28 with magnesium in a suitable solvent such as THF,optionally in the presence of catalytic amounts of iodine attemperatures ranging from 0° C. to the boiling point of the solvent(step d).

Compounds 25 can be further converted into compounds 26 by adeoxyfluorination reaction using a suitable fluorinating agent such asDAST, Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) oraminodifluorosulfinium tetrafluoroborates (XtalFluor-E®, XtalFluor-M® inthe presence of, e.g. triethylamine trihydrofluoride and TEA or DBU) ina suitable solvent such as DCM or ACN (step d).

Removal of the protective group from intermediates 26 applyingliterature methods and as described for example under Scheme 3, step c,furnishes intermediates E (step e).

In a further embodiment, intermediates 2 are intermediates of type F.Intermediates F in which A, m, n, R² and R³ are as described herein, canbe prepared by methods well known in the art and as exemplified by thegeneral synthetic procedures outlined in Scheme 9. In case R³ is ahydroxy group a suitable protective group strategy known to thoseskilled in the art may be applied.

The carboxylic acid functionality in intermediates 29, eithercommercially available or prepared by methods known in the art, in whichPG signifies a suitable protecting group such as, e.g. a Boc, Cbz or Bnprotecting group, can be converted for example into an acid chloride(LG=Cl) or Weinreb amide (LG=NMeOMe) by applying methods broadlydescribed in literature to give intermediates 30 (step a).

Intermediates 30 can be reacted with compounds of type 31, eithercommercially available or synthesized by methods known in the art and asdescribed below to yield intermediates 32 (step b).

In case compounds 31 are commercially not available they can be preparedin analogy to literature methods. For example, deprotonation ofoptionally substituted aryl or heteroaryl rings 33 using an appropriatebase such n-BuLi, sec-BuLi, tert-BuLi, LiHMDS, NaH, KH in a suitablesolvent, such as THF, n-hexane or mixtures thereof, at temperaturesranging from −78° C. to room temperature, gives intermediates 31 inwhich, depending on the base used, MX=Li, Na or K (step c).

Compounds 31 in which MX=MgHal with Hal being Cl, Br or I (Grignardreagents) may be prepared by reaction of the corresponding optionallysubstituted aryl or heteroaryl halides 34 via direct insertion ofmagnesium (e.g. magnesium turnings optionally in the presence ofcatalytic amounts of iodine, powder in the presence of LiCl or Riekemagnesium, organic halides) or by halogen-magnesium exchange by treating34 in which Hal is preferably bromine or iodine, with an alkylmagnesiumhalide such as iPrMgCl (optionally in the presence of LiCl) in suitablesolvents such as diethyl ether or THF at temperatures ranging from 0° C.to the boiling point of the solvent (step d).

Compounds 32 can be further converted into compounds 35 by adeoxyfluorination reaction using a suitable fluorinating agent such asDAST, Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) oraminodifluorosulfinium tetrafluoroborates (XtalFluor-E®, XtalFluor-M® inthe presence of, e.g. triethylamine trihydrofluoride and TEA or DBU) ina suitable solvent such as DCM or ACN (step e).

Removal of the protective group from intermediates 35 applyingliterature methods and as described for example under Scheme 3, step c,furnishes intermediates F (step f).

In some embodiments, intermediates 2 are intermediates of type G.Intermediates of type G in which A, m, n, R² are as described herein andR³ is hydrogen, C₁₋₆-alkoxy, C₁₋₆-alkyl and halo-Ct-6-alkyl, can beprepared by methods well known in the art and as exemplified by thegeneral synthetic procedures outlined in Scheme 10.

Intermediates 38 may be prepared from alcohols 36 in which PG is asuitable protective group such as a Cbz, Boc or Bn, that can bealkylated with compounds 37 in which LG is a suitable leaving group suchas chlorine, bromine, iodine, OSO₂alkyl (e.g. methanesulfonate),OSO₂fluoroalkyl (e.g. trifluoromethanesulfonate) or OSO₂aryl (e.g.p-toluenesulfonate) using a suitable base, such as sodium hydride,potassium tert-butoxide, in an appropriate solvent (e.g. in DMF or THF)at temperatures between 0° C. and the boiling temperature of the solvent(step a).

Removal of the protective group from intermediates 38 applyingliterature methods and as described for example under Scheme 4, step c,furnishes intermediates G (step b).

In some embodiments, intermediates 2 are intermediates of type H.Intermediates of type H in which A, m, n, R² and R³ are as describedherein, can be prepared by methods well known in the art and asexemplified by the general synthetic procedures outlined in Scheme 11.

Alcohols of type 17 can be subjected to a Mitsunobu reaction withintermediates 39 in which PG is a suitable protective group such as aCbz, Boc or Bn, using an appropriate phosphine such astriphenylphosphine and a dialkyl azodicarboxylate such as DEAD or DIADin a suitable solvent such as THF to give intermediates 41 (step a).Mitsunobu reactions of that type are broadly described in literature(e.g. Org. Chem. Front. 2015, 2, 739; Chem. Rev. 2009, 109 (6), 2551).

Removal of the protective group from intermediates 41 applyingliterature methods and as described for example under Scheme 4, step c,furnishes intermediates H (step b).

Alternatively, intermediates 41 may be prepared from alcohols 17 thatcan be alkylated with compounds 40 in which LG is a suitable leavinggroup such as chlorine, bromine, iodine, OSO₂alkyl (e.g.methanesulfonate), OSO₂fluoroalkyl (e.g. trifluoromethanesulfonate) orOSO₂aryl (e.g. p-toluenesulfonate) using a suitable base such as Cs₂CO₃,NaH, in an appropriate solvent, such as DMF at temperatures between 0°C. and the boiling temperature of the solvent (step c).

Reacting intermediates H with intermediates 1, for example using theconditions described under scheme 1, step a, affords compounds of typeIf, wherein A, R¹, R², R³, m and n are as defined herein.

Alternatively, compounds of type If may be prepared according to Scheme12.

Alcohols of type 17 can be subjected to a Mitsunobu reaction withintermediates 42, using an appropriate phosphine such astriphenylphosphine and a dialkyl azodicarboxylate such as DEAD or DIADin a suitable solvent such as THF to give compounds ID (step a).Mitsunobu reactions of that type are broadly described in literature(e.g. Org. Chem. Front. 2015, 2, 739; Chem. Rev. 2009, 109 (6), 2551).

Alternatively, compounds ID may be directly prepared from alcohols 17that can be alkylated with compounds 43 in which LG is a suitableleaving group such as chlorine, bromine, iodine, OSO₂alkyl (e.g.methanesulfonate), OSO₂fluoroalkyl (e.g. trifluoromethanesulfonate) orOSO₂aryl (e.g. p-toluenesulfonate) using a suitable base such as Cs₂CO₃,NaH, in an appropriate solvent, such as DMF at temperatures between 0°C. and the boiling temperature of the solvent (step b).

In some embodiments, intermediates 2 are intermediates of type J.Intermediates of type J in which A, m, n, R² and R³ are as describedherein, can be prepared by methods well known in the art and asexemplified by the general synthetic procedures outlined in Scheme 13.

Intermediates 46 may be prepared from heterocycloalkyls or heteroaryls45 that can be alkylated with compounds 44 in which LG is a suitableleaving group such as chlorine, bromine, iodine, OSO₂alkyl (e.g.methanesulfonate), OSO₂fluoroalkyl (e.g. trifluoromethanesulfonate) orOSO₂aryl (e.g. p-toluenesulfonate) using a suitable base such as Cs₂CO₃,K₂CO₃, NaH, in an appropriate solvent, such as DMF at temperaturesbetween 0° C. and the boiling temperature of the solvent (step a).

Removal of the protective group from intermediates 46 applyingliterature methods and as described for example under Scheme 4, step c,furnishes intermediates J (step b).

Reacting intermediates J with intermediates 1 affords compounds of typeIg, wherein A, R¹, R², R³, m and n are as defined herein.

Alternatively, compounds of type Ig may be directly prepared from fromheterocycloalkyls or heteroaryls 45 that can be alkylated with compounds47 in which LG is a suitable leaving group such as chlorine, bromine,iodine, OSO₂alkyl (e.g. methanesulfonate), OSO₂fluoroalkyl (e.g.trifluoromethanesulfonate) or OSO₂aryl (e.g. p-toluenesulfonate) using asuitable base such as Cs₂CO₃, K₂CO₃, NaH, in an appropriate solvent,such as DMF at temperatures between 0° C. and the boiling temperature ofthe solvent (Scheme 14).

In some embodiments, intermediates 2 are intermediates of type K.Intermediates of type K in which A, m, n, R² and R³ are as describedherein, can be prepared by methods well known in the art and asexemplified by the general synthetic procedures outlined in Scheme 15.

Alcohols of type 48 can be subjected to a Mitsunobu reaction withintermediates 39 in which PG is a suitable protective group such as aCbz, Boc or Bn, using an appropriate phosphine such astriphenylphosphine and a dialkyl azodicarboxylate such as DEAD or DIADin a suitable solvent such as THF to give intermediates 49 (step a).Mitsunobu reactions of that type are broadly described in literature(e.g. Org. Chem. Front. 2015, 2, 739; Chem. Rev. 2009, 109 (6), 2551).

Removal of the protective group from intermediates 49 applyingliterature methods and as described for example under Scheme 4, step c,furnishes intermediates K (step b).

Alternatively, intermediates 49 may be prepared from alcohols 48 thatcan be alkylated with compounds 40 in which LG is a suitable leavinggroup such as chlorine, bromine, iodine, OSO₂alkyl (e.g.methanesulfonate), OSO₂fluoroalkyl (e.g. trifluoromethanesulfonate) orOSO₂aryl (e.g. p-toluenesulfonate) using a suitable base such as Cs₂CO₃,NaH, in an appropriate solvent, such as DMF at temperatures between 0°C. and the boiling temperature of the solvent (step c).

In some embodiments, intermediates 2 are intermediates of type L.Intermediates of type L in which A, m, n, R² and R³ are as describedherein can be prepared by methods well known by a person skilled in theart and as exemplified by the general synthetic procedures outlined inScheme 16.

Intermediates 51 can be prepared for example from aldehydes 50, eithercommercially available or prepared by methods known in the art, using aWittig reaction or Homer-Wadsworth-Emmons (HWE) reaction usingalkylidene triphenylphosphoranes of type 8a and phosphonates 8b,respectively, as described under step a in Scheme 4 (step a).

Reduction of the double bond in intermediates 51 applying the conditionsdescribed under step b in Scheme 4 yields compounds 52 (step b).

Removal of the protective group from intermediates 52 applying methodsknown in the art and as outlined under step c in Scheme 4 furnishesintermediates L (step c).

Removal of the protective group from intermediates 51 applying methodsknown in the art and as outlined under step c in Scheme 4 furnishesintermediates M (step d).

In one aspect, the present invention provides a process of manufacturingthe urea compounds of formula (I) described herein, comprising:

-   -   reacting a first amine of formula 1, wherein R¹ is as described        herein, preferably wherein R¹ is hydrogen,

-   -   with a second amine 2, wherein A, L, m, n, X and R² are as        described herein

-   -   in the presence of a base and a urea forming reagent,

to form said compound of formula (I).

In one embodiment, there is provided a process according to theinvention, wherein said base is sodium bicarbonate.

In one embodiment, there is provided a process according to theinvention, wherein said urea forming reagent is selected frombis(trichloromethyl) carbonate, phosgene, trichloromethyl chloroformate,(4-nitrophenyl)carbonate and 1,1′-carbonyldiimidazole, preferablywherein said urea forming reagent is bis(trichloromethyl) carbonate.

In one aspect, the present invention provides a compound of formula (I)as described herein, when manufactured according to any one of theprocesses described herein. MAGL Inhibitory Activity

Compounds of the present invention are MAGL inhibitors. Thus, in oneaspect, the present invention provides the use of compounds of formula(I) as described herein for inhibiting MAGL in a mammal.

In a further aspect, the present invention provides compounds of formula(I) as described herein for use in a method of inhibiting MAGL in amammal.

In a further aspect, the present invention provides the use of compoundsof formula (I) as described herein for the preparation of a medicamentfor inhibiting MAGL in a mammal.

In a further aspect, the present invention provides a method forinhibiting MAGL in a mammal, which method comprises administering aneffective amount of a compound of formula (I) as described herein to themammal.

Compounds were profiled for MAGL inhibitory activity by measuring theenzymatic activity of MAGL by following the hydrolysis of4-nitrophenylacetate resulting in 4-nitrophenol, which absorbs at405-412 nm (G. G. Muccioli, G. Labar, D. M. Lambert, Chem. Bio. Chem.2008, 9, 2704-2710). This assay is hereinafter abbreviated “4-NPAassay”.

The 4-NPA assay was carried out in 384 well assay plates (black withclear bottom, non-binding surface treated, Corning Ref. 3655) in a totalvolume of 40 μL. Compound dilutions were made in 100% DMSO (VWRChemicals 23500.297) in a polypropylene plate in 3-fold dilution stepsto give a final concentration range in the assay from 25 μM to 1.7 nM. 1μL compound dilutions (100% DMSO) were added to 19 μL MAGL (recombinantwild-type) in assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA(Fluka, 03690-100 ml)). The plate was shaked for 1 min at 2000 rpm(Variomag Teleshake) and then incubated for 15 min at RT. To start thereaction, 20 μL 4-Nitrophenlyacetate (Sigma N-8130) in assay buffer with6% EtOH was added. The final concentrations in the assay were 1 nM MAGLand 300 μM 4-Nitrophenylacetate. After shaking (1 min, 2000 rpm) and 5min incubation at RT, the absorbance at 405 nm was measured for a firsttime (Molecular Devices, SpectraMax Paradigm). A second measurement wasthen done after incubation for 80 min at RT. From the two measurements,the slope was calculated by subtracting the first from the secondmeasurement.

Alternatively, compounds were profiled for MAGL inhibitory activity bydetermining the enzymatic activity by following the hydrolysis of thenatural substrate 2-arachidonoylglycerol resulting in arachidonic acid,which can be followed by mass spectrometry. This assay is hereinafterabbreviated “2-AG assay”.

The 2-AG assay was carried out in 384 well assay plates (PP, Greiner Cat#784201) in a total volume of 20 μL. Compound dilutions were made in100% DMSO (VWR Chemicals 23500.297) in a polypropylene plate in 3-folddilution steps to give a final concentration range in the assay from12.5 μM to 0.8 μM. 0.25 μL compound dilutions (100% DMSO) were added to9 μL MAGL in assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA(Fluka, 03690-100 ml), 0.01% (v/v) Tween. After shaking, the plate wasincubated for 15 min at RT. To start the reaction, 10 μL2-arachidonoylglycerol in assay buffer was added. The finalconcentrations in the assay was 50 μM MAGL and 8 μM2-arachidonoylglyerol. After shaking and 30 min incubation at RT, thereaction was quenched by the addition of 40 μL of acetonitrilecontaining 4 μM of d8-arachidonic acid. The amount of arachidonic acidwas traced by an online SPE system (Agilent Rapidfire) coupled to atriple quadrupole mass spectrometer (Agilent 6460). A C18 SPE cartridge(G9205A) was used in an acetonitrile/water liquid setup. The massspectrometer was operated in negative electrospray mode following themass transitions 303.1→259.1 for arachidonic acid and 311.1→267.0 ford8-arachidonic acid. The activity of the compounds was calculated basedon the ratio of intensities [arachidonic acid/d8-arachidonic acid].

TABLE 1 Ex. IC₅₀ MAGL [μM]^([a]) 1 0.040 2 0.046 3 0.066 4 0.092 5 1.3 65.7 7 0.011 8 0.013 9 0.035 10 0.039 11 0.042 12 0.077 13 0.087 14 0.19115 0.190 16 0.208 17 0.268 18 0.892 19 1.5 20 1.8 21 0.909 22 2.1 230.856 24 0.004 25 0.452 26 0.684 27 0.007 28 0.018 29 0.005 30 0.273 310.049 32 0.020 33 0.004 34 0.438 35 0.019 36 0.119 37 1.3 38 0.160 390.116 40 0.012 42 1.2 43 0.529 44 0.038 45 0.850 46 0.005 47 0.005 480.288 49 0.363 50 0.008 51 0.010 52 0.058 53 0.006 54 0.001 55 0.079 560.042 57 0.049 58 0.003 59 0.012 60 0.680 61 0.011 62 0.009 64 0.040 660.351 67 0.120 72 0.108 73 0.008 74 0.003 75 0.002 76 0.008 77 0.016 790.001 81 0.006 87 0.006^([b]) 88 0.005^([b]) 89 0.034^([b]) 900.168^([b]) 91 0.099^([b]) 92 0.014^([b]) 93 0.124 94 0.150 95 0.008 960.293 97 0.146 98 0.010 99 0.012 100 0.082 101 0.011 102 0.022 103 0.005104 0.451 105 0.285 108 0.001 109 0.223 110 2.179 111 0.020 112 0.012113 0.005 114 0.005 115 0.003 116 0.004 117 0.010 118 0.132^([b]) 1190.014^([b]) 120 0.007^([b]) 121 0.151^([b]) 122 0.008^([b]) 1230.082^([b]) 124 1.035^([b]) 139 0.002^([b]) 140 0.059^([b]) 1410.040^([b]) 142 0.075^([b]) 201 0.239^([b]) 202 0.054^([b]) 2030.871^([b]) 204 0.100^([b]) 205 0.086^([b]) 206 0.023^([b]) 2070.050^([b]) 208 0.003^([b]) 209 0.074^([b]) 210 0.080^([b]) 2110.017^([b]) 212 0.003^([b]) 213 0.098^([b]) 214 0.036^([b]) 2150.005^([b]) 216 0.006^([b]) 217 0.010^([b]) 218 0.003^([b]) 2190.002^([b]) 220 0.003^([b]) 221 0.0007^([b]) 222 0.143^([b]) 2230.075^([b]) 224 0.003^([b]) 225 0.007^([b]) 226 0.045^([b]) 2270.067^([b]) 228 0.126^([b]) 229 0.0009^([b]) 230 0.073^([b]) 2310.005^([b]) 232 0.061^([b]) 233 0.022^([b]) 234 0.002^([b]) 2350.033^([b]) 236 0.175^([b]) 237 0.254^([b]) 238 0.002^([b]) 2390.0004^([b]) 240 0.016^([b]) 241 0.015^([b]) 242 0.012^([b]) 2430.010^([b]) 244 0.030^([b]) 245 1.7^([b]) 246 1.0^([b]) 247 1.1^([b])248 0.607^([b]) 249 0.005^([b]) 250 0.008^([b]) 251 0.005^([b]) 2520.005^([b]) 253 0.010^([b]) 254 0.064^([b]) 255 0.010^([b]) 2560.011^([b]) 257 0.014^([b]) 258 0.048^([b]) 259 0.015^([b]) 2600.018^([b]) 261 0.048^([b]) 262 0.181^([b]) 263 1.1^([b]) 2640.084^([b]) 265 0.006^([b]) 266 0.018^([b]) 267 0.042^([b]) 2680.028^([b]) 269 0.024^([b]) 270 0.061^([b]) 271 0.020^([b]) 2720.094^([b]) 273 0.089^([b]) 274 0.126^([b]) 275 0.032^([b]) 2760.019^([b]) 277 0.455^([b]) 278 0.211^([b]) 279 0.001^([b]) 2800.041^([b]) 281 0.035^([b]) 282 0.136^([b]) 283 0.179^([b]) 2840.072^([b]) 285 2.6^([b]) 286 0.128^([b]) 287 0.006^([b]) 2880.053^([b]) 289 0.003^([b]) 290 0.044^([b]) 291 0.028^([b]) 2920.005^([b]) 293 0.030^([b]) 294 3.0^([b]) ^([a])if not indicatedotherwise (see [b]), the activity was measured in 4-NPA assay;^([b])measured in 2-AG assay.

In one aspect, the present invention provides compounds of formula (I)and their pharmaceutically acceptable salts or esters as describedherein, wherein said compounds of formula (I) and their pharmaceuticallyacceptable salts or esters have IC₅₀'s for MAGL inhibition below 25 μM,preferably below 10 μM, more preferably below 5 μM as measured in theMAGL assay described herein.

In one embodiment, compounds of formula (I) and their pharmaceuticallyacceptable salts or esters as described herein have IC₅₀ (MAGLinhibition) values between 0.000001 μM and 25 μM, particular compoundshave IC₅₀ values between 0.000005 μM and 10 μM, further particularcompounds have IC₅₀ values between 0.00005 μM and 5 μM, as measured inthe MAGL assay described herein.

In one embodiment, the present invention provides compounds of formula(I) and their pharmaceutically acceptable salts or esters as describedherein, wherein said compounds of formula (I) and their pharmaceuticallyacceptable salts or esters have an IC₅₀ for MAGL below 25 μM, preferablybelow 10 μM, more preferably below 5 μM as measured in an assaycomprising the steps of:

-   -   a) providing a solution of a compound formula (I), or a        pharmaceutically acceptable salt or ester thereof, in DMSO;    -   b) providing a solution of MAGL (recombinant wild-type) in assay        buffer (50 mM tris(hydroxymethyl)aminomethane; 1 mM        ethylenediaminetetraacetic acid);    -   c) adding 1 μL of compound solution from step a) to 19 μL of        MAGL solution from step b);    -   d) shaking the mixture for 1 min at 2000 rpm;    -   e) incubating for 15 min at RT;    -   f) adding 20 μL of a solution of 4-nitrophenlyacetate in assay        buffer (50 mM tris(hydroxymethyl)aminomethane; 1 mM        ethylenediaminetetraacetic acid, 6% EtOH);    -   g) shaking the mixture for 1 min at 2000 rpm;    -   h) incubating for 5 min at RT;    -   i) measuring the absorbance of the mixture at 405 nm a first        time;    -   j) incubating a further 80 min at RT;    -   k) measuring the absorbance of the mixture at 405 nm a second        time;    -   l) subtracting the absorbance measured under i) from the        absorbance measured under k) and calculating the slope of        absorbance;    -   wherein:    -   i) the concentration of the compound of formula (I), or the        pharmaceutically acceptable salt or ester thereof in the assay        after step f) is in the range of 25 μM to 1.7 nM;    -   ii) the concentration of MAGL in the assay after step f) is 1        nM;    -   iii) the concentration of 4-nitrophenylacetate in the assay        after step f) is 300 μM; and    -   iv) steps a) to 1) are repeated for at least 3 times, each time        with a different concentration of the compound of formula (I),        or the pharmaceutically acceptable salt or ester thereof.

Using the Compounds of the Invention

In one aspect, the present invention provides compounds of formula (I)as described herein for use as therapeutically active substance.

In a further aspect, the present invention provides the use of compoundsof formula (I) as described herein for the treatment or prophylaxis ofneuroinflammation, neurodegenerative diseases, pain, cancer and/ormental disorders in a mammal.

In one embodiment, the present invention provides the use of compoundsof formula (I) as described herein for the treatment or prophylaxis ofneuroinflammation and/or neurodegenerative diseases in a mammal.

In one embodiment, the present invention provides the use of compoundsof formula (I) as described herein for the treatment or prophylaxis ofneurodegenerative diseases in a mammal.

In one embodiment, the present invention provides the use of compoundsof formula (I) as described herein for the treatment or prophylaxis ofcancer in a mammal.

In one aspect, the present invention provides the use of compounds offormula (I) as described herein for the treatment or prophylaxis ofmultiple sclerosis, Alzheimer's disease, Parkinson's disease,amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity,stroke, epilepsy, anxiety, migraine, depression, hepatocellularcarcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain,chemotherapy induced neuropathy, acute pain, chronic pain and/orspasticity associated with pain in a mammal.

In a preferred embodiment, the present invention provides the use ofcompounds of formula (I) as described herein for the treatment orprophylaxis of multiple sclerosis, Alzheimer's disease and/orParkinson's disease in a mammal.

In a particularly preferred embodiment, the present invention providesthe use of compounds of formula (I) as described herein for thetreatment or prophylaxis of multiple sclerosis in a mammal.

In one aspect, the present invention provides compounds of formula (I)as described herein for use in the treatment or prophylaxis ofneuroinflammation, neurodegenerative diseases, pain, cancer and/ormental disorders in a mammal.

In one embodiment, the present invention provides compounds of formula(I) as described herein for use in the treatment or prophylaxis ofneuroinflammation and/or neurodegenerative diseases in a mammal.

In one embodiment, the present invention provides compounds of formula(I) as described herein for use in the treatment or prophylaxis ofcancer in a mammal.

In one embodiment, the present invention provides compounds of formula(I) as described herein for use in the treatment or prophylaxis ofneurodegenerative diseases in a mammal.

In one aspect, the present invention provides compounds of formula (I)as described herein for use in the treatment or prophylaxis of multiplesclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy,anxiety, migraine, depression, hepatocellular carcinoma, coloncarcinogenesis, ovarian cancer, neuropathic pain, chemotherapy inducedneuropathy, acute pain, chronic pain and/or spasticity associated withpain in a mammal.

In a preferred embodiment, the present invention provides compounds offormula (I) as described herein for use in the treatment or prophylaxisof multiple sclerosis, Alzheimer's disease and/or Parkinson's disease ina mammal.

In a particularly preferred embodiment, the present invention providescompounds of formula (I) as described herein for use in the treatment orprophylaxis of multiple sclerosis in a mammal.

In one aspect, the present invention provides the use of compounds offormula (I) as described herein for the preparation of a medicament forthe treatment or prophylaxis of neuroinflammation, neurodegenerativediseases, pain, cancer and/or mental disorders in a mammal.

In one embodiment, the present invention provides the use of compoundsof formula (I) as described herein for the preparation of a medicamentfor the treatment or prophylaxis of neuroinflammation and/orneurodegenerative diseases in a mammal.

In one embodiment, the present invention provides the use of compoundsof formula (I) as described herein for the preparation of a medicamentfor the treatment or prophylaxis of neurodegenerative diseases in amammal.

In one embodiment, the present invention provides the use of compoundsof formula (I) as described herein for the preparation of a medicamentfor the treatment or prophylaxis of cancer in a mammal.

In a further aspect, the present invention provides the use of compoundsof formula (I) as described herein for the preparation of a medicamentfor the treatment or prophylaxis of multiple sclerosis, Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis, traumaticbrain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine,depression, hepatocellular carcinoma, colon carcinogenesis, ovariancancer, neuropathic pain, chemotherapy induced neuropathy, acute pain,chronic pain and/or spasticity associated with pain in a mammal.

In a preferred embodiment, the present invention provides the use ofcompounds of formula (I) as described herein for the preparation of amedicament for the treatment or prophylaxis of multiple sclerosis,Alzheimer's disease and/or Parkinson's disease in a mammal.

In a particularly preferred embodiment, the present invention providesthe use of compounds of formula (I) as described herein for thepreparation of a medicament for the treatment or prophylaxis of multiplesclerosis in a mammal.

In one aspect, the present invention provides a method for the treatmentor prophylaxis of neuroinflammation, neurodegenerative diseases, pain,cancer and/or mental disorders in a mammal, which method comprisesadministering an effective amount of a compound of formula (I) asdescribed herein to the mammal.

In one embodiment, the present invention provides a method for thetreatment or prophylaxis of neuroinflammation and/or neurodegenerativediseases in a mammal, which method comprises administering an effectiveamount of a compound of formula (I) as described herein to the mammal.

In one embodiment, the present invention provides a method for thetreatment or prophylaxis of neurodegenerative diseases in a mammal,which method comprises administering an effective amount of a compoundof formula (I) as described herein to the mammal.

In one aspect, the present invention provides a method for the treatmentor prophylaxis of multiple sclerosis, Alzheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, traumatic brain injury,neurotoxicity, stroke, epilepsy, anxiety, migraine, depression and/orpain in a mammal, which method comprises administering an effectiveamount of a compound of formula (I) as described herein to the mammal.

In a preferred embodiment, the present invention provides a method forthe treatment or prophylaxis of multiple sclerosis, Alzheimer's diseaseand/or Parkinson's disease in a mammal, which method comprisesadministering an effective amount of a compound of formula (I) asdescribed herein to the mammal.

In a particularly preferred embodiment, the present invention provides amethod for the treatment or prophylaxis of multiple sclerosis in amammal, which method comprises administering an effective amount of acompound of formula (I) as described herein to the mammal.

Pharmaceutical Compositions and Administration

In one aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) as described herein anda therapeutically inert carrier.

The compounds of formula (I) and their pharmaceutically acceptable saltsand esters can be used as medicaments (e.g. in the form ofpharmaceutical preparations). The pharmaceutical preparations can beadministered internally, such as orally (e.g. in the form of tablets,coated tablets, dragées, hard and soft gelatin capsules, solutions,emulsions or suspensions), nasally (e.g. in the form of nasal sprays) orrectally (e.g. in the form of suppositories). However, theadministration can also be effected parentally, such as intramuscularlyor intravenously (e.g. in the form of injection solutions).

The compounds of formula (I) and their pharmaceutically acceptable saltsand esters can be processed with pharmaceutically inert, inorganic ororganic adjuvants for the production of tablets, coated tablets, dragéesand hard gelatin capsules. Lactose, corn starch or derivatives thereof,talc, stearic acid or its salts etc. can be used, for example, as suchadjuvants for tablets, dragées and hard gelatin capsules.

Suitable adjuvants for soft gelatin capsules are, for example, vegetableoils, waxes, fats, semi-solid substances and liquid polyols, etc.

Suitable adjuvants for the production of solutions and syrups are, forexample, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable adjuvants for injection solutions are, for example, water,alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural orhardened oils, waxes, fats, semi-solid or liquid polyols, etc.

Moreover, the pharmaceutical preparations can contain preservatives,solubilizers, viscosity-increasing substances, stabilizers, wettingagents, emulsifiers, sweeteners, colorants, flavorants, salts forvarying the osmotic pressure, buffers, masking agents or antioxidants.They can also contain still other therapeutically valuable substances.

The dosage can vary in wide limits and will, of course, be fitted to theindividual requirements in each particular case. In general, in the caseof oral administration a daily dosage of about 0.1 mg to 20 mg per kgbody weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g.about 300 mg per person), divided into preferably 1-3 individual doses,which can consist, for example, of the same amounts, should beappropriate. It will, however, be clear that the upper limit givenherein can be exceeded when this is shown to be indicated.

In accordance with the invention, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of type 2 diabetes related microvascularcomplications (such as, but not limited to diabetic retinopathy,diabetic neuropathy and diabetic nephropathy), coronary artery disease,obesity and underlying inflammatory diseases, chronic inflammatory andautoimmune/inflammatory diseases.

EXAMPLES

The invention will be more fully understood by reference to thefollowing examples. The claims should not, however, be construed aslimited to the scope of the examples.

In case the preparative examples are obtained as a mixture ofenantiomers, the pure enantiomers can be separated by methods describedherein or by methods known to the man skilled in the art, such as e.g.,chiral chromatography (e.g., chiral SFC) or crystallization.

All reaction examples and intermediates were prepared under an argonatmosphere if not specified otherwise.

Method A1 Example 11rac-(4aR,8aS)-6-[4-[[4-(Trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

To a solution of 4-nitrophenyl4-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (100 mg, 245 μmol,BB2) in DMF (1.5 mL),rac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-onedihydrochloride (45.9 mg, 294 μmol, ChemBridge Corporation, BB1) and TEA(49.6 mg, 68.3 μL, 490 μmol) were added. The resultant reaction mixturewas heated at 80° C. for 18 h. The reaction mixture was diluted withEtOAc and washed three times with H₂O and NaHCO₃. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, eluting with a gradient of MeOH/EtOAc 0-10%)to afford the title compound as an off-white oil (0.045 g; 43.2%). MS(ESI): m/z=426.4 [M+H]⁺.

Method A2 Example 3rac-(4aR,8aS)-6-[4-[(4-tert-Butylthiazol-2-yl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

To an ice-cold suspension of bis(trichloromethyl) carbonate (45.3 mg,153 μmol, CAS RN 32315-10-9) and NaHCO₃ (73.3 mg, 873 μmol) in DCM (2mL) was added in one portion 4-tert-butyl-2-(4-piperidylmethyl)thiazolehydrochloride (60 mg, 218 μmol, Enamine Ltd) and the mixture was stirredat RT overnight. The suspension was filtered and the filtrate wasevaporated. The residue was diluted in DCM (1 mL) and added dropwise toan ice-cold solution ofrac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-onedihydrochloride (50 mg, 218 μmol, ChemBridge Corporation, BB1) and DIPEA(152 μL, 870 μmol) in DCM (1 mL). The suspension was stirred at RT for19 h to become a solution. The reaction mixture was poured on H₂O andDCM and the layers were separated. The aqueous layer was extracted threetimes with DCM. The organic layers were washed twice with water, driedover MgSO₄, filtered, treated with silica gel and evaporated. Thecompound was purified by silica gel chromatography on a 4 g column usingan MPLC system eluting with a gradient of DCM:MeOH (100:0 to 90:10) toprovide the desired compound as a colorless foam (0.039 g; 42.5%). MS(ESI): m/z=421.2 [M+H]⁺.

Method A3 Example 34 (+)- or(−)-4-[[1-[(4aR,8aS)-3-Oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-4-piperidyl]methyl]benzonitrile

To an ice-cold solution of bis(trichloromethyl) carbonate (39.9 mg, 134μmol, CAS RN 32315-10-9) in DCM were added NaHCO₃ (64.5 mg, 768 μmol)and (+)-cis-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (30 mg, 192μmol, BB1a) and the mixture was stirred at RT overnight. To thesuspension was added 4-(piperidin-4-ylmethyl)benzonitrile (38.5 mg, 192μmol, CAS RN 333987-57-8) and DIPEA (99.3 mg, 134 μL, 768 μmol). Thesuspension was stirred at RT for 4.5 h. The reaction mixture was pouredon H₂O and DCM and the layers were separated. The aqueous layer wasextracted three times with DCM. The organic layers were washed twicewith H₂O, dried over MgSO₄, filtered, treated with silica gel andevaporated. The compound was purified by silica gel chromatography on a4 g column using an MPLC system eluting with a gradient of DCM:MeOH(100:0 to 90:10) to furnish the desired compound as a colorless gum(0.023 g; 31.3%). MS (ESI): m/z=383.2 [M+H]⁺.

Method A4 Example 79(4aR,8aS)-6-(4-((2-chloro-4-fluorophenoxy)methyl)-4-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

To a solution of 4-nitrophenyl(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate(25 mg, 77.8 μmol, BB7a) in NMP (1 mL) was added DIPEA (25.1 mg, 34 μL,195 μmol) and 4-((2-chloro-4-fluorophenoxy)methyl)-4-methylpiperidine;hydrochloride salt (19.5 mg, 66.1 μmol, BB12). The reaction vial wasstirred at 140° C. for 45 min. The crude material was purified byreversed-phase HPLC to yield 23.2 mg of the desired product. MS (ESI):m/z=440.2 [M+H]⁺.

Method A5 Example 64(4aR,8aS)-6-(4-((2-Chloro-4-fluorophenoxy)methyl)-4-fluoropiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

A microwave vial was heat gun-dried and charged withbis(trichloromethyl) carbonate (26.6 mg, 89.6 μmol) and sodiumbicarbonate (32.3 mg, 384 μmol). The flask was placed under argon andDCM (1 mL) was added to give a suspension. The suspension was cooled byan ice-bath and 4-((2-chloro-4-fluorophenoxy)methyl)-4-fluoropiperidine;hydrochloride salt (36.1 mg, 121 μmol, BB15) was added. The mixture wasstirred at 0° C. for 15 min and at RT overnight. The reaction mixturewas cooled down in an-ice bath and DCM (500 μL) and DIPEA (49.7 mg, 67.1μL, 384 μmol) followed by(4aR,8aS)-6-(4-((2-chloro-4-fluorophenoxy)methyl)-4-fluoropiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one(21.1 mg, 47.5 μmol, BB1a) were added. The resulting off-whitesuspension was stirred at room temperature for 7 h. The reaction mixturewas poured on water, DCM was added and the layers were separated. Theaqueous layer was extracted twice with DCM. The combined organic layerswere washed with brine, dried over MgSO₄, filtered and evaporated toafford a yellow oil (58 mg). The crude product was purified byreverse-phase HPLC and lyophilized to provide the title compound as awhite solid (21.1 mg, 37.1% yield). MS (ESI): m/z=444.2 [M+H]⁺.

Method A6 Example 39(4aR,8aS)-6-[4-[(2-Fluoro-4-methoxyphenoxy)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

To a solution of 2-fluoro-4-methoxyphenol (16.5 mg, 13 μL, 116 μmol),(4aR,8aS)-6-[4-(hydroxymethyl)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one(34.5 mg, 116 μmol, BB16) and triphenylphosphine (33.5 mg, 128 μmol) inDCM (580 μL) was added DIAD (25.8 mg, 24.8 μL, 128 μmol) dropwise andthe reaction was stirred at room temperature for 22 h. The reactionmixture was diluted with DCM and washed with 1M aq. NaOH. The phaseswere separated and the aq. phase was extracted with DCM twice. Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated to dryness to give a red oil (99 mg). The crude product waspurified by reverse-phase HPLC and lyophilized to afford the desiredcompound (20 mg, 40.9% yield) as a white solid. MS (ESI):m/z=422.3[M+H]⁺.

Method A7 Example 42 and 43(4aS,8aR)-6-(4-(((6-(Trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one(Example 42) and(4aR,8aS)-6-(4-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one(Example 43)

Step a)rac-(4aR,8aS)-6-(4-(Chloromethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

To a solution ofrac-(4aR,8aS)-6-(4-(hydroxymethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one(80 mg, 269 μmol, BB16) in dry DMF (2 mL) was added DIPEA (52.2 mg, 70.5μL, 404 μmol), DMAP (1.64 mg, 13.5 μmol) and methanesulfonyl chloride(46.2 mg, 404 μmol) and the reaction mixture was stirred at roomtemperature for 2 h. Addition of 4,4-difluoropiperidine; hydrochloridesalt (84.8 mg, 538 μmol), DIPEA (139 mg, 188 μL, 1.08 mmol) and thereaction mixture was stirred at room temperature for 2 h. The reactionwas then stirred at 70° C. for 14 h. The crude reaction was submittedfor reversed-phase HPLC purification to yield the title compound as aside product (35 mg). MS (ESI): m/z=315.1 [M+H]⁺.

Step b)(4aS,8aR)-6-(4-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one(Example 42) and(4aR,8aS)-6-(4-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one(Example 43)

To a solution ofrac-(4aR,8aS)-6-(4-(chloromethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one(70 mg, 222 μmol) in dry DMF (1 mL) was added6-(trifluoromethyl)pyridin-3-ol (54.2 mg, 332 μmol) and Cs₂CO₃ (108 mg,332 μmol). The reaction mixture was stirred at 95° C. for 18 h.Insolubles were removed by filtration over Celite, the filtrate wasconcentrated down to dryness and the crude residue was purified and theenantiomers separated by chiral SFC to yield Example 42 (33.8 mg) andExample 43 (32.5 mg). MS (ESI): m/z=443.2 [M+H]⁺ for both examples.

Method A8 Example 26(4aS,8aR)-6-(4-((4-(Trifluoromethyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

To a solution ofrac-(4aR,8aS)-6-(4-(hydroxymethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one(75 mg, 252 μmol, BB16) in dry DMF (2 mL) was added DIPEA (39.1 mg, 52.9μL, 303 μmol), DMAP (3.08 mg, 25.2 μmol) and methanesulfonyl chloride(30.3 mg, 265 μmol) and the reaction mixture was stirred at roomtemperature for 2 h. 4-(Trifluoromethyl)-1H-pyrazole (68.6 mg, 504 μmol)and K₂CO₃ (87.1 mg, 631 μmol) were added and the reaction mixture wasstirred at 90° C. for 18 h. Insolubles were removed by filtration overcelite, the filtrate was concentrated to dryness in vacuo and the cruderesidue was directly purified by flash chromatography with an eluentmixture of DCM and MeOH (0% to 10%), to yield 90 mg of the desiredproduct as a racemate. This was submitted for SFC chiral separation toyield Example 26 (25 mg) as a colorless oil and the enantiomer (31 mg)as a colorless oil. MS (ESI): m/z=416.2 [M+H]⁺.

Method A9 Example 37(4aR,8aS)-6-(4-((4,4-Difluoropiperidin-1-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

To a solution of(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (40 mg, 256μmol, BB1a) in dry DMF (2 mL) cooled down to 0° C. was added DIPEA (39.7mg, 53.7 μL, 307 μmol) and 4-nitrophenyl carbonochloridate (61.9 mg, 307μmol). The reaction mixture was stirred at 0° C. for 20 min. LCMScontrol showed formation of the intermediate carbamate. DIPEA (116 mg,157 μL, 896 μmol) and 4,4-difluoro-1-(piperidin-4-ylmethyl)piperidine;dihydrochloride salt (89.5 mg, 307 μmol, BB17) were added and thereaction mixture was then stirred at room temperature for 30 min, thenstirred at 100° C. for 14 h. Volatiles were removed in vacuo and thecrude residue was directly submitted for SFC purification to yield thedesired compound (9.5 mg) as a light orange oil. MS (ESI): m/z=401.3[M+H]⁺.

Method A10 Example 125(+)-(4aR,8aS)-6-[4-[2-(2-Chlorophenyl)ethynyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

In a sealed tube, 4-[2-(2-chlorophenyl)ethynyl]piperidine (BB18, 0.02 g,0.078 mmol) and 4-nitrophenyl(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate(BB7a, 0.025 g, 0.078 mmol) were mixed in ACN (0.6 mL). Then, Huenig'sbase (0.041 mL, 0.234 mmol) was added, followed by DMAP (0.005 g, 0.039mmol) and the reaction mixture was heated to 90° C. overnight. Themixture was evaporated to dryness and the crude residue purified byreverse phase HPLC to give the title compound (0.013 g, 41%) as acolorless solid. MS (ESI): m/z=402.2 [M+H]⁺.

Method B1 Example 1(+)-(4aR,8aS)-6-(4-((4-(tert-Butyl)thiazol-2-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

The enantiomers of example 3 were separated by preparative chiral HPLC(Chiralcel OD column) using an isocratic mixture of EtOH (containing0.05% of NH₄OAc):n-heptane (20:80). The fractions were evaporated toprovide the desired compound as a colorless solid (0.012 g; 34.3%). MS(ESI): m/z=421.2 [M+H]⁺.

Method B2 Example 12 (+)- or(−)-(4aR,8aS)-6-(4-(4-(Trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

The enantiomers of example 13 were separated using preparative chiralHPLC (Chiralpak AD column) using an isocratic mixture of EtOH(containing 0.05% of NH₄OAc):n-heptane (40:60). The fractions wereevaporated to yield the desired compound as a light brown oil (0.013 g;28.4%). MS (ESI): m/z=428.2 [M+H]⁺.

Method B3 Examples 103, 104 and 105(4aR,8aS)-6-[2-Methyl-3-[[4-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one(Isomer A+B, Isomer C, Isomer D)

The stereoisomers of example 117 were separated by preparative chiralHPLC (Reprosil Chiral NR column) using an isocratic mixture of EtOH(containing 0.05% of NH₄OAc):n-heptane (40:60) to provide examples 103and 104 as single isomers and example 105 as mixture of twostereoisomers. The fractions were evaporated to provide the desiredcompounds as colorless solids.

Method C Example 21rac-(4aR,8aS)-6-(4-(4-(Trifluoromethyl)benzyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

A mixture ofrac-cis-6-(piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one(35 mg, 130 μmol, BB3), 4-(trifluoromethyl)benzaldehyde (22.7 mg, 17.4μL, 130 μmol) and sodium triacetoxyborohydride (27.6 mg, 130 μmol) inDCM (1 mL) was stirred at RT for 15 h. The reaction mixture wasconcentrated and the residue was purified by preparative HPLC to givethe desired compound as a white solid (8 mg, 14.40%). MS (ESI):m/z=427.4 [M+H]⁺.

If not indicated otherwise the following examples were synthesized fromrac-(4aR,8aB)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-onedihydrochloride (ChemBridge Corporation) and the suitable buildingblocks in analogy to the reaction methods described herein.

Ex. Systematic Name/Structure Building block(s) MS, m/z Method 2

Example 4 405.3 [M + H]⁺ B1 4

Supplier of building block: BCH Research (UK) and BB1 405.4 [M + H]⁺ A25

Example 3 421.2 [M + H]⁺ B1 6

Example 4 405.3 [M + H]⁺ B1 7

Supplier of building block: UkrOrgSyntez Ltd. and BB1 426.2 [M + H]⁺ A28

Example 11 426.4 [M + H]⁺ B1 9

4-[(4-Chlorophenoxy) methylpiperidine (CAS RN 63608-33-3) and BB1 408.3[M + H]⁺ A2 10

4-(4-Chloro-benzyl)- piperidine hydrochloride (CAS RN 36938-76-8) andBB1 392.2 [M + H]⁺ A2 13

4-(4- Trifluoromethylphenoxy) piperidine hydrochloride (CAS RN28033-37-6) and BB1 428.2 [M + H]⁺ A2 14

Example 17 426.3 [M + H]⁺ B1 15

BB4 and BB1 374.4 [M + H]⁺ A1 16

FCH Group and BB1 405.2 [M + H]⁺ A2 17

4-(4-Trifluoromethyl benzyl) piperidine HCl (CAS RN 192990-03-7) and BB6426.3 [M + H]⁺ A2 18

3-Phenyl-5-(piperidin-4- ylmethyl)-1,2,4-oxadiazole (CAS RN1239730-22-3) and BB1 426.3 [M + H]⁺ A2 19

Example 17 426.4 [M + H]⁺ B1 20

Example 11 426.4 [M + H]⁺ B1 22

1-(4-Chlorobenzyl)-piperazine (CAS RN 23145-88-2) and BB1 393.2 [M + H]⁺A2 23

Example 7 426.2 [M + H]⁺ B1 24

Example 7 426.2 [M + H]⁺ B1 25

BB5 and BB1 427.2 [M + H]⁺ A2 27

Supplier of building block: HDH Pharma, Inc. and BB1 432.2 [M + H]⁺ A228

Supplier of building block: ZereneX Molecular Limited and BB1a 398.1[M + H]⁺ A2 29

Example 27 432.2 [M + H]⁺ B1 30

Example 27 432.2 [M + H]⁺ B1 31

4-[4-(Trifluoromethoxy) benzyl]piperidine (CAS RN 681482-50-8) and BB1a442.2 [M + H]⁺ A2 32

4-((2,4-Difluorophenoxy) methyl)piperidine HCl CAS RN 614731-39-4 andBB1a 410.2 [M + H]⁺ A5 33

Building block prepared as described in WO2013/179024 and BB1a 410.2[M + H]⁺ A2 35

4-(4-Chloro-benzyl)- piperidine hydrochloride (CAS RN 36938-76-8) andBB1a 392.2 [M + H]⁺ A2 36

3-[[4-(Trifluoromethyl) phenyl]methyl]azetidine (CAS RN 937614-88-5) andBB1a 398.3 [M + H]⁺ A1 38

BB8 and BB1a 405.3 [M + H]⁺ A2 40

BB9 and BB1a 462.1 [M + H]⁺ A2 41

BB19 and BB1a  495.18 [M + H]⁺ A3 44

4-(3-Trifluoromethyl) phenoxy)piperidine (CAS RN 337912-66-0) and BB1a428.2 [M + H]⁺ A3 45

2-Chloro-4- (trifluoromethoxy)phenol (CAS: 35852-58-5) and BB1b 492.2[M + H]⁺ A6 46

2-Chloro-4- (trifluoromethoxy)phenol (CAS RN: 35852-58-5) and BB1a 492.2[M + H]⁺ A6 47

BB20 and BB1a 432.2 [M + H]⁺ A5 48

BB12 and BB7b 440.2 [M + H]⁺ A4 (1:1 ACN: iPrOH) 49

4-[(2,4- Difluorophenoxy)methyl] piperidine hydrochloride (CAS RN:614731-39-4) and BB7b 410.2 [M + H]⁺ A4 50

4-Chloro-2-fluorophenyl 4- piperidinylmethyl ether; hydrochloride salt(CAS: 946680-87-1) and BB7A 426.2 [M + H]⁺ A4 (microwave heating) 51

BB21 and BB7a 460.2 [M + H]⁺ A4 52

BB22 and BB7a 460.2 [M + H]⁺ A4 53

BB91 and BB1a 495.3 [M + H]⁺ A3 54

BB23 and BB1a 476.3 [M + H]⁺ A5 55

BB24 and BB1a 417.2 [M + H]⁺ A5 56

1-[[2-(Pyrrolidin-1-yl)-4- (trifluoromethyl)phenyl] methyl]piperazine(synthesized according to WO2015/179559) and BB1a  496.26 [M + H]⁺ A3 57

BB25 and BB1a 398.2 [M + H]⁺ A5 58

BB10 and BB1a 494.3 [M + H]⁺ A3 59

BB26 and BB1a 433.2 [M + H]⁺ A5 60

BB27 and BB1a 416.3 [M + H]⁺ A9 61

BB28 and BB1a 406.3 [M + H]⁺ A5 62

BB29 and BB1a 448.2 [M + H]⁺ A5 63

BB30 and BB1a 445.24 [M + H]⁺ A3 65

BB31 and BB1a  401.22 [M + H]⁺ A3 66

BB32 and BB1a 404.3 [M + H]⁺ A9 (purified by RP- HPLC) 67

4-(4-Trifluoromethyl benzyl)piperidine HCl (CAS RN 192990-03-7) and BB33440.3 [M + H]⁺ A3 68

BB34 and BB1a  495.18 [M + H]⁺ A3 69

BB35 and BB1a  495.11 [M + H]⁺ A3 followed by RP- HPLC 70

BB35 and BB1a  461.16 [M + H]⁺ A3 followed by RP- HPLC 71

BB35 and BB1a 427.2 [M + H]⁺ A3 followed by RP- HPLC 72

BB11 and BB7a 399.2 [M + H]⁺ A1 73

BB13 and BB7a 504.1 [M + H]⁺ A1 74

BB36 and BB1a 440.1 [M + H]⁺ A3 75

BB7a and BB37 448.2 [M + H]⁺ A4 (solvent ACN instead of NMP) 76

BB7a and BB38 414.2 [M + H]⁺ A4 (solvent ACN instead of NMP) 77

BB7a and BB39 448.2 [M + H]⁺ A4 (solvent ACN instead of NMP) 78

BB7a and BB40 411.2 [M + H]⁺ A4 (solvent ACN not NMP) 80

BB41 and BB1a 509.2 [M + H]⁺ A3 81

BB14 and BB7a 492.2 [M + H]⁺ A1 82

BB42 and BB1a 509.2 [M + H]⁺ A3 83

BB43 and BB1a  517.18 [M + H]⁺ A3 84

BB44 and BB1a  517.18 [M + H]⁺ A3 85

N-methyl-N-(piperidin-4-yl)- 4-(trifluoromethyl)benzamide hydrochloride(CAS RN 1580795-67-0) and BB1a  469.20 [M + H]⁺ A3 86

BB94 and BB1a  483.22 [M + H]⁺ A3 87

BB88 and BB1a 414.3 [M + H]⁺ A5 88

BB45 and BB1a 444.3 [M + H]⁺ A4 (ACN as solvent) 89

BB46 and BB1a 457.2 [M + H]⁺ A3 90

3-[(3-Chlorophenoxy) methyl]pyrrolidine (CAS RN 914299-54-0) and BB1a 394.15 [M + H]⁺ A4 (ACN as solvent) 91

BB47 and BB1a  394.15 [M + H]⁺ A4 (ACN as solvent) 92

BB48 and BB1a 444.2 [M + H]⁺ A4 (ACN as solvent) 93

BB49 and BB1a  394.15 [M + H]⁺ A4 (ACN as solvent) 94

BB50 and BB1a  394.15 [M + H]⁺ A4 (ACN as solvent) 95

BB51 and BB1a  466.23 [M + H]⁺ A4 (ACN as solvent) 96

BB52 and BB1a  394.15 [M + H]⁺ A4 (ACN as solvent) 97

BB53 and BB1a  394.15 [M + H]⁺ A4 (ACN as solvent) 98

BB54 and BB1a 440.4 [M + H]⁺ A3 99

BB55 and BB1a  460.16 [M + H]⁺ A3 100

3-(4-Trifluoromethylbenzyl) pyrrolidine hydrochloride salt (CAS RN:957988-84-4) and BB1a  412.19 [M + H]⁺ A3 101

BB56 and BB1a 432.2 [M + H]⁺ A4 (ACN as solvent) 102

BB1a and BB57 446.3 [M + H]⁺ A4 (ACN as solvent) 103

Example 117  428.19 [M + H]⁺ B3 104

Example 117  428.19 [M + H]⁺ B3 105

Example 117  428.19 [M + H]⁺ B3 106

BB58 and BB1a  455.19 [M + H]⁺ A3 107

BB59 and BB1a  523.22 [M + H]⁺ A3 108

BB60 and BB1a 448.2 [M + H]⁺ A4 (1:1 iPrOH: ACN as solvent) 109

BB61 and BB1a 416.2 [M + H]⁺ A4 (1:1 iPrOH: ACN as solvent) 110

BB62 and BB1a 500.2 [M + H]⁺ A4 (ACN as solvent) 111

BB63 and BB1a 446.2 [M + H]⁺ A4 (ACN as solvent) 112

BB64 and BB1a 450.2 [M + H]⁺ A4 (ACN as solvent) 113

BB65 and BB1a 432.2 [M + H]⁺ A4 (ACN as solvent) 114

BB66 and BB1a 432.2 [M + H]⁺ A4 (ACN as solvent) 115

BB67 and BB1a 444.3 [M + H]⁺ A4 (ACN as solvent) 116

BB68 and BB1a 448.2 [M + H]⁺ A4 (1:1 iPrOH: ACN as solvent) 117

BB69 and BB1a  428.18 [M + H]⁺ A3 118

BB70 and BB1a 400.2 [M + H]⁺ A4 (ACN as solvent) 119

BB71 and BB1a 462.2 [M + H]⁺ A4 (ACN as solvent) 120

BB72 and BB1a 434.1 [M + H]⁺ A4 (ACN as solvent) 121

BB73 and BB1a 479.2 [M + H]⁺ A4 (ACN as solvent) 122

BB74 and BB1a 442.1 [M + H]⁺ Hans A4 (ACN as solvent) 123

BB75 and BB1a 453.0 [M + H]⁺ Hans A4 (ACN as solvent) 124

BB76 and BB1a 400.2 [M + H]⁺ A4 (ACN as solvent) 126

BB77 403.3 [M + H]⁺ A10 127

BB78 403.2 [M + H]⁺ A10 128

BB79 420.3 [M + H]⁺ A10 129

BB80 402.3 [M + H]⁺ A10 130

BB81 402.3 [M + H]⁺ A10 131

BB82 436.3 [M + H]⁺ A10 132

BB83 418.4 [M + H]⁺ A10 133

BB84 374.2 [M + H]⁺ A10 134

BB85 408.3 [M + H]⁺ A10 135

BB86 392.2 [M + H]⁺ A10 136

BB92 413.2 [M + H]⁺ A1 (ACN as solvent DIPEA as base) 137

BB93 441.2 [M + H]⁺ A1 (ACN as solvent DIPEA as base) 139

BB95 430.4 [M + H]⁺ A1 (ACN as solvent DIPEA as base) 140

BB96  440.18 [M + H]⁺ A3 followed by chiral SFC 141

BB96  440.18 [M + H]⁺ A3 followed by chiral SFC 142

BB97 440.2 [M + H]⁺ A3 143

BB98 and BB1a 450.1 [M + H]⁺ A3 144

BB99 and BB1a 482.2 [M + H]⁺ A3 145

BB100 and BB1a 466.2 [M + H]⁺ A3 146

Example 145 466.2 [M + H]⁺ SFC, Chiral- pak AD, 40% MeOH 147

Example 145 466.2 [M + H]⁺ SFC, Chiral- pak AD, 40% MeOH 148

BB101 and BB1a 464.1 [M + H]⁺ A3 152

BB104 and BB1a 496.1 [M + H]⁺ A3 153

BB105 and BB1a 480.1 [M + H]⁺ A3 154

Example 153 480.1 [M + H]⁺ A3, then HPLC Reprosil Chiral NR, 60%heptane, 40% EtOH + NH₄Ac 155

Example 153 480.1 [M + H]⁺ A3, then HPLC Reprosil Chiral NR, 60%heptane, 40% EtOH + NH₄Ac 156

BB106 and BB1a 448.1 [M + H]⁺ A3 157

BB107 408.2 [M + H]⁺ A10 158

BB108 426.3 [M + H]⁺ A10 159

BB109 376.3 [M + H]⁺ A10 160

BB110 442.3 [M + H]⁺ A10 161

BB111 392.3 [M + H]⁺ A10 162

BB112 414.4 [M + H]⁺ A10 163

BB113 370.4 [M + H]⁺ A10 164

BB114 442.3 [M + H]⁺ A10 165

BB115 374.3 [M + H]⁺ A10 166

BB116 424.3 [M + H]⁺ A10 167

BB117 408.4 [M + H]⁺ A10 168

BB118 372.2 [M + H]⁺ A10 169

BB119 368.4 [M + H]⁺ A10 170

BB120 424.3 [M + H]⁺ A10 171

BB121 420.3 [M + H]⁺ A10 172

BB122 392.3 [M + H]⁺ A10 173

BB123 354.3 [M + H]⁺ A10 174

BB124 392.3 [M + H]⁺ A10 175

BB125 406.3 [M + H]⁺ A10 176

BB126 399.3 [M + H]⁺ A10 177

BB127 406.3 [M + H]⁺ A10 178

BB128 405.4 [M + H]⁺ A10 179

BB129 380.4 [M + H]⁺ A10 180

BB130 396.4 [M + H]⁺ A10 181

BB131 370.3 [M + H]⁺ A10 182

BB132 390.3 [M + H]⁺ A10 183

BB133 384.3 [M + H]⁺ A10 184

BB134 388.3 [M + H]⁺ A10 185

BB135 392.2 [M + H]⁺ A10 186

BB136 418.3 [M + H]⁺ A10 187

BB137 380.2 [M + H]⁺ A10 188

BB138 380.2 [M + H]⁺ A10 189

BB139 460.3 [M + H]⁺ A10 190

BB140 390.3 [M + H]⁺ A10 191

BB141 384.3 [M + H]⁺ A10 192

BB143 436.4 [M + H]⁺ A10 193

BB144 398.4 [M + H]⁺ A10 194

BB145 382.4 [M + H]⁺ A10 195

BB146 396.4 [M + H]⁺ A10 196

BB147 450.3 [M + H]⁺ A10 197

BB148 434.4 [M + H]⁺ A10 198

BB149 330.3 [M − H₂O + H]⁺ A10 199

BB149 (Elimination product isolated during synthesis of example 198)330.3 [M + H]⁺ A10 200

BB142 442.3 [M + H]⁺ A10 201

BB7a and BB98 494.2 [M + H]⁺ A4 202

BB7a and BB99 524.2 [M + H]⁺ A4 203

BB7a and BB100 495.2 [M + H]⁺ A4 204

BB7a and BB101 434.1 [M + H]⁺ A4 205

BB7a and BB102 460.2 [M + H]⁺ A4 206

BB7a and BB103 513.3 [M + H]⁺ A4 207

BB7a and BB104 461.2 [M + H]⁺ A4 208

BB7a and BB105 468.2 [M + H]⁺ A4 209

BB7a and BB106 494.3 [M + H]⁺ A4 210

BB7a and 4-(4- Chlorophenoxy)piperidine hydrochloride (CAS RN63843-53-8) 394.1 [M + H]⁺ A4 211

BB7a and BB107 462.2 [M + H]⁺ A4 212

BB7a and BB108 522.2 [M + H]⁺ A4 213

BB7a and BB109 434.1 [M + H]⁺ A4 214

BB7a and BB110 432.1 [M + H]⁺ A4 215

BB7a and BB111 376.0 [M + H]⁺ A4 216

BB7a and BB112 442.3 [M + H]⁺ A4 217

BB7a and BB113 428.3 [M + H]⁺ A4 218

BB7a and BB114 442.1 [M + H]⁺ A4 219

BB7a and BB115 426.1 [M + H]⁺ A4 220

BB7a and BB116 454.3 [M + H]⁺ A4 221

BB7a and BB117 491.0 [M + H]⁺ A4 224

BB170 and BB1a 414.1 [M + H]⁺ A3 225

BB171 and BB1a 414.1 [M + H]⁺ A3 226

BB173 and BB1a 429.4 [M + H]⁺ A3 227

BB173 and BB1a 442.2 [M + H]⁺ A3 Chiral HPLC (Reprosil Chiral NR, 60% n-heptane, 40% EtOH + NH₄Ac 228

BB173 and BB1a 442.2 [M + H]⁺ A3 Chiral HPLC (Reprosil Chiral NR, 60% n-heptane, 40% EtOH + NH₄Ac 229

BB173 and BB1a 442.2 [M + H]⁺ A3 Chiral HPLC (Reprosil Chiral NR, 60% n-heptane, 40% EtOH + NH₄Ac 230

BB174 and BB1a 415.2 [M + H]⁺ A3 231

BB175 and BB1a 471.2 [M + H]⁺ A3 SFC: OD- H column, 20% EtOH 232

BB175 and BB1a 471.2 [M + H]⁺ A3 SFC: OD- H column, 20% EtOH 233

BB176 and BB1a 464.2 [M + H]⁺ A3 234

BB177 and BB1a 483.2 [M + H]⁺ A3 235

BB178 and BB1a 464.1 [M + H]⁺ A3 HPLC: YMC- Triart C18, 25- 45-60- 100%ACN in water 236

Example 233 464.4 [M + H]⁺ Reprosil Chiral NR, 70% Heptan, 30% EtOH +NH₄Ac 237

Example 233 464.3 [M + H]⁺ Reprosil Chiral NR, 70% Heptan, 30% EtOH +NH₄Ac 238

Example 233 464.4 [M + H]⁺ Reprosil Chiral NR, 70% n- heptane, 30%EtOH + NH₄Ac 239

BB179 and BB1a 472.2 [M + H]⁺ A3 240

BB180 and BB1a 490.1 [M + H]⁺ A3 241

BB181 and BB1a 454.3 [M + H]⁺ A3 242

BB182 and BB1a 525.3 [M + H]⁺ A3 243

BB183 and BB1a 525.3 [M + H]⁺ A3 244

BB184 and BB1a 447.2 [M + H]⁺ A3 245

BB185 and BB1a 514.2 [M + H]⁺ A3 246

BB186 and BB1a 508.1 [M + H]⁺ A3 247

Example 246 508.0 [M + H]⁺ HPLC: Reprosil Chiral NR, 60% n- heptane, 40%EtOH + NH₄Ac 248

Example 246 508.0 [M + H]⁺ HPLC: Reprosil Chiral NR, 60% n- heptane, 40%EtOH + NH₄Ac 249

BB7a and BB187 482.1 [M + H]⁺ A10 250

BB7a and BB188 428.3 [M + H]⁺ A10 251

BB7a and BB189 444.2 [M + H]⁺ A10 252

BB7a and BB190 458.2 [M + H]⁺ A10 253

BB7a and BB191 442.3 [M + H]⁺ A10 254

BB7a and BB192 446.3 [M + H]⁺ A10 255

BB7a and BB193 462.3 [M + H]⁺ A10 256

BB194 406.4 [M + H]⁺ A10 257

BB7a and BB195 462.3 [M + H]⁺ A10 258

BB7a and BB196 446.0 [M + H]⁺ A10 259

BB7a and BB197 406.4 [M + H]⁺ A10 260

BB7a and BB199 440.1 [M + H]⁺ A10 261

BB7a and BB200 434.1 [M + H]⁺ A10 262

BB7a and BB202 453.4 [M + H]⁺ A10 264

BB7a and BB205 444.2 [M + H]⁺ A10 279

BB7a and BB206 430.2 [M + H]⁺ A4 ACN as solvent followed by prep- HPLC280

BB7a and BB207 432.2 [M + H]⁺ A4 ACN as solvent followed by prep- HPLC281

BB7a and BB208 448.3 [M + H]⁺ A4 ACN as solvent followed by prep- HPLC282

BB7a and 3-(3- (Trifluoromethoxy) benzyl) azetidine hydrochloride (CASRN 1354963-49-7) 414.3 [M + H]⁺ A4 ACN as solvent followed by prep- HPLC283

BB7a and BB209 432.2 [M + H]⁺ A4 ACN as solvent followed by MPLC (n-heptane: EtOAc/ EtOH 3/1 (70:30 to 10:90) 284

BB7a and BB210 448.2 [M + H]⁺ A4 ACN as solvent followed by MPLC (n-heptane: EtOAc/ EtOH 3/1 (70:30 to 10:90) 285

Example 283 432.2 [M + H]⁺ B3 286

Example 283 432.2 [M + H]⁺ B3 287

BB1a and BB211 374.2 [M + H]⁺ A3 288

BB7a and BB212 448.3 [M + H]⁺ A4 289

BB1a and BB213 428.2 [M + H]⁺ A3 290

BB7a and BB214 374.2 [M + H]⁺ A4 (ACN as solvent) 291

BB7a and BB215 374.2 [M + H]⁺ A4 (ACN as solvent) 292

BB7a and BB 216 428.2 [M + H]⁺ A4 (ACN as solvent) 293

Example 216 427.2 [M + H]⁺ G 294

BB217 428.2 [M + H]⁺ A3 295

BB1a and BB218 448.1 [M + H]⁺ A3

Example 222(4aR,8aS)-6-[3-[[6-Fluoro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

Step a) tert-Butyl3-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carboxylate

To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate(CAS Nr. 142253-56-3) (2.60 g, 13.9 mmol) and2,6-dichloro-4-(trifluoromethyl)pyridine (CAS Nr. 39890-98-7) (3.00 g,13.9 mmol) in THF (60 mL) was added NaH (60%, 1.11 g, 27.8 mmol) and themixture was stirred 3 h at 25° C. The solution was poured into sat. aq.NH₄Cl (50 mL) and extracted with EtOAc (2×50 mL). The combined organiclayers were concentrated under vacuum to give crude tert-butyl3-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carboxylate(3.00 g, 59%) as colorless oil, which was used directly in the nextstep. LC-MS (ESI): m/z=367.1 [M+H]⁺.

Step b) 2-(Azetidin-3-ylmethoxy)-6-chloro-4-(trifluoromethyl)pyridine

A solution of trifluoroacetic acid (6.3 mL, 81.8 mmol, 10 eq) andtert-butyl3-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carboxylate(3.00 g, 8.18 mmol) in DCM (30 mL) was stirred at 25° C. for 4 h. Thesolution was concentrated under vacuum to give a residue, which waspurified by Prep-HPLC (HCl condition) to give2-(azetidin-3-ylmethoxy)-6-chloro-4-(trifluoromethyl)pyridine (1.00 g,46%) as white solid. LC-MS (ESI): m/z=267.0 [M+H]⁺.

Step c)(4aR,8aS)-6-[3-[[6-Chloro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][,4]oxazin-3-one

A solution of2-(azetidin-3-ylmethoxy)-6-chloro-4-(trifluoromethyl)pyridine (150 mg,0.560 mmol), N,N-diisopropylethylamine (0.29 mL, 1.69 mmol) and4-nitrophenyl(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate(BB7a) (199 mg, 0.620 mmol) in ACN (5 mL) was stirred at 25° C. for 16h. The solution was concentrated under vacuum to give a residue, whichwas purified by prep-HPLC (TFA conditions) to give(4aR,8aS)-6-[3-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one(100 mg, 40%) as colorless oil. LC-MS (ESI): m/z=449.2 [M+H]⁺.

Step d)(4aR,8aS)-6-[3-[[6-Fluoro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

A solution of(4aR,8aS)-6-[3-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one(75 mg, 0.17 mmol) and cesium fluoride (101 mg, 0.670 mmol) in DMSO (3mL) was stirred at 80° C. for 16 h. The solution was filtered andpurified by prep-HPLC (TFA conditions) to give(4aR,8aS)-6-[3-[[6-fluoro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one(22 mg, 28%) as white solid. LC-MS (ESI): m/z=433.0 [M+H]⁺.

Example 223(4aR,8aS)-6-[3-[[6-Fluoro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

Step a) tert-Butyl3-[[6-chloro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carboxylate

To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate(CAS Nr. 142253-56-3) (1.56 g, 8.33 mmol) in THF (50 mL) was added NaH(60%, 741 mg, 18.5 mmol) followed by2,6-dichloro-3-(trifluoromethyl)pyridine (CAS Nr. 55304-75-1) (2.00 g,9.26 mmol). The resulting mixture was stirred at 25° C. for 3 h. Thesolution was poured into sat.aq. NH₄Cl (50 mL) and extracted with EtOAc(2×30 mL). The combined organic layers were concentrated under vacuum togive a residue, which was purified by flash column chromatography(petroleum ether:EtOAc=5:1) to give tert-butyl3-[[6-chloro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carboxylate(1.10 g, 32%) as colorless oil. LC-MS (ESI): m/z=311.0 [M−56+H]⁺.

Step b) 6-(Azetidin-3-ylmethoxy)-2-chloro-3-(trifluoromethyl)pyridine

A solution of trifluoroacetic acid (0.37 mL, 4.8 mmol) and tert-butyl3-[[6-chloro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carboxylate(1.1 g, 3.0 mmol) in DCM (30 mL) was stirred at 25° C. for 4 h. Thesolution was concentrated under vacuum to give a residue, which waspurified by Prep-HPLC (HCl condition) to give6-(azetidin-3-ylmethoxy)-2-chloro-3-(trifluoromethyl)pyridine (600 mg,75%) as white solid. LC-MS (ESI): m/z=267.0 [M+H]⁺.

Step c)(4aR,8aS)-6-[3-[[6-Chloro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

To a solution of6-(azetidin-3-ylmethoxy)-2-chloro-3-(trifluoromethyl)pyridine (100 mg,0.380 mmol) and 4-nitrophenyl(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate(BB7a) (120 mg, 0.380 mmol) in ACN (5 mL) was addedN,N-diisopropylethylamine (0.13 mL, 0.75 mmol) with stirring at 25° C.The solution was stirred at 25° C. for 16 h. The solution wasconcentrated under vacuum to give a residue, which was purified byPrep-HPLC (TFA conditions) to give(4aR,8aS)-6-[3-[[6-chloro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one(76 mg, 45%) as white solid. LC-MS (ESI): m/z=449.1 [M+H]⁺.

Step d)(4aR,8aS)-6-[3-[[6-Fluoro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

A solution of(4aR,8aS)-6-[3-[[6-chloro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one(70 mg, 0.16 mmol) and cesium fluoride (95 mg, 0.62 mmol) in DMSO (3 mL)was stirred at 60° C. for 24 h. The solution was filtered and thenpurified by Prep-HPLC (TFA conditions) to give(4aR,8aS)-6-[3-[[6-fluoro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one(38 mg, 49%) as white solid. LC-MS (ESI): m/z=433.3 [M+H]⁺.

Synthesis of Building Blocks BB1a & BB1b(+)-cis-4a,5,6,7,8,8a-Hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one and(−)-cis-4a,5,6,7,8,8a-Hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one

The enantiomers ofrac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-onedihydrochloride (BB1, 500 mg, 2.18 mmol, ChemBridge Corporation) wereseparated by preparative chiral HPLC (ReprosilChiral NR column) using anisocratic mixture of EtOH (containing 0.05% of NH₄OAc):n-heptane(30:70).

First eluting enantiomer:(+)-cis-4a,5,6,7,8,8a-Hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one(BB1a). Yellow solid (0.150 g; 44.0%). MS (ESI): m/z=157.1 [M+H]⁺.

Second eluting enantiomer:(−)-cis-4a,5,6,7,8,8a-Hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one.(BB1b). Yellow solid (0.152 g; 44.6%). MS (ESI): m/z=157.1 [M+H]⁺.

BB2 (4-Nitrophenyl)4-[[4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate

To a solution of 4-(4-(trifluoromethyl)benzyl)piperidine (100 mg, 411μmol, CAS RN 192990-03-7) in DCM (1 mL), TEA (83.2 mg, 115 μL, 822 μmol)was added. On cooling to 0° C., 4-nitrophenyl carbonochloridate (91.1mg, 452 μmol, CAS RN 7693-46-1) was added, the reaction mixture wasallowed to warm to RT and stirred for 18 hours. The reaction mixture wasdiluted with DCM and subsequently washed with H₂O and sat. aqueousNaHCO₃ solution. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica 10 g, eluting withEtOAc/Heptane 0-50%), to afford title compound as a light yellow solid.(0.165 g; 98.3%). MS (ESI): m/z=409.3 [M+H]⁺.

BB3rac-(4aR,8aS)-6-(Piperazine-1-carbonyl)-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

To a mixture of rac-tert-butyl4-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperazine-1-carboxylate(100 mg, 271 μmol) in DCM (3 mL) was added TFA (155 mg, 105 μL, 1.36mmol) and the mixture was stirred at RT for 15 h under an argonatmosphere. The reaction mixture was washed with a saturated aqueousNaHCO₃ solution. The H₂O layer was concentrated in vacuo to give a whitesolid which was triturated with DCM for 30 min. before it was filtered.The filtrate was concentrated to give a light yellow gum (70 mg, 96.1%).MS (ESI): m/z=269.3 [M+H]⁺.

Step a) rac-tert-Butyl4-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperazine-1-carboxylate

To a mixture of triphosgene (1.29 g, 4.36 mmol) and Na₂CO₃ (1.98 g, 18.7mmol) in THF (3 mL) at 0° C. were added dropwise a solution oftert-butyl piperazine-1-carboxylate (1.16 g, 6.23 mmol, CAS RN57260-71-6) in THF (90 mL). The reaction mixture was stirred for 10 min.at 0° C., then allowed to warm up to RT and stirring was continued at RTfor 5 h. The suspension was filtered off and the filtrate wasconcentrated in vacuo. The residue was dissolved in THF (40 mL) andadded dropwise to a stirred suspension ofrac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-onehydrochloride (1200 mg, 6.23 mmol, Chembridge Corporation) and DIPEA(4.83 g, 6.53 mL, 37.4 mmol) in THF (40 mL) at 0° C. After 30 min. at 0°C., the reaction mixture was allowed to warm up to RT, and stirred at RTfor 15 h. The mixture was filtered and the filtrate concentrated invacuo. The residue was diluted with DCM and washed with water, aq.NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated to give a white solid (1.13 g, 58.6%). MS(ESI): m/z=313.3 [M+H]⁺.

BB4 (4-Nitrophenyl) 4-(phenoxymethyl)piperidine-1-carboxylate

The compound was prepared in analogy to BB2 using4-(phenoxymethyl)piperidine (CAS N63614-86-8) to afford title compoundas a white solid which was used in the next step without furtherpurification.

BB5

2-(4-Piperidylmethyl)-5-(trifluoromethyl)pyridine; Hydrochloride Salt

tert-Butyl4-[[5-(trifluoromethyl)-2-pyridyl]methyl]piperidine-1-carboxylate (320mg, 0.930 mmol) was dissolved in 4 M HCl in EtOAc (10.0 mL, 40 mmol) andthe solution stirred at 20° C. for 2 h. The mixture was concentrated toyield the desired compound as light yellow solid (0.259, 94.8%). MS(ESI): m/z=245.0 [M−HCl+H]⁺.

Step a) tert-Butyl4-[[5-(trifluoromethyl)-2-pyridyl]methyl]piperidine-1-carboxylate

2-Bromo-5-(trifluoromethyl)pyridine (500.0 mg, 2.21 mmol, CAS RN1000773-62-5) was degassed before 9-BBN solution 0.5 M in THF (4.87 mL,2.43 mmol, CAS RN 280-64-8) was added. The resulting solution wasrefluxed for 1 h. After cooling to RT, the solution was added to asolution of tert-butyl 4-methylenepiperidine-1-carboxylate (480.1 mg,2.43 mmol, CAS RN 159635-49-1),[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride (161.89mg, 0.220 mmol, CAS RN 72287-26-4) and K₂CO₃ (611.56 mg, 4.42 mmol) inDMF (5 mL) and water (0.5 mL). The resulting mixture was heated at 80°C. for 4 h. The mixture was cooled to RT and poured into water, the pHwas adjusted to 11 with 10% aqueous NaOH and the mixture was extractedwith EtOAc. The combined organic extracts were washed with brine, driedover Na₂SO4, filtered, and evaporated to give a crude oil, which waspurified by column chromatography (silica adsorbent; gradient ofPE:EtOAc 10:1 then 5:1) to yield the desired compound as a light yellowoil (320 mg, 0.930 mmol, 42%). MS (ESI): m/z=289.0 [M-C₄H8+H]⁺.

BB6 rac-(4aS,8aS)-Hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

rac-Benzyl(4aS,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate(125 mg, 431 μmol) was dissolved in MeOH (5 mL). The reaction solutionwas degassed in vacuo and backfilled with argon. Pd—C (20 mg, 188 μmol)was added under an argon atmosphere. Argon was evacuated from thereaction mixture and backfilled with hydrogen. The reaction mixture wasstirred at RT for 15 h under a hydrogen atmosphere. The reaction mixturewas filtered through a syringe filter and concentrated in vacuo toafford the desired product as a white solid (62 mg, 92.2%). MS (ESI):m/z=157.098 [M+H]⁺.

Step a) rac-Benzyl(3S,4S)-3-(2-chloroacetamido)-4-hydroxypiperidine-1-carboxylate

To a stirred suspension of rac-benzyl(3S,4S)-3-amino-4-hydroxypiperidine-1-carboxylate (317 mg, 1.27 mmol,synthesized according to patent US 2011/59118 A1) and sodium acetate(208 mg, 2.53 mmol, CAS RN 127-09-3) in a mixture of acetone (4 mL)/H₂O(0.5 mL) was added dropwise a solution of chloroacetyl chloride (150 mg,107 μL, 1.33 mmol, CAS RN 79-04-9) in acetone (3 mL) between 0-5° C.After the addition the reaction mixture was stirred at RT for 1 h andsubsequently evaporated to dryness giving a yellow gum. The crudeproduct was purified by silica gel chromatography to afford the desiredproduct as a yellow solid (385 mg, 93%). MS (ESI): m/z=325.2 [M−H]³¹.

Step b) rac-Benzyl(4aS,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate

To a stirred solution of rac-Benzyl(3S,4S)-3-(2-chloroacetamido)-4-hydroxypiperidine-1-carboxylate (385 mg,1.18 mmol) in dry THF (4 mL) was added NaH (67.9 mg, 1.7 mmol) at 0° C.The mixture was allowed to reach RT and then stirred for 90 min under anargon atmosphere. H₂O (5 mL) was added and stirring was continued for 10min at RT. THF was removed in vacuo from the reaction mixture. Theresidue was treated with DCM and the organic phase was washed with H₂Oand brine, dried over Na₂SO₄, filtered and then concentrated in vacuo.The residue was purified by flash chromatography (12 g reversed phasecolumn, gradient 0-100% ACN (0.1% FA) in water (0.1% FA) to afford thedesired product as a white solid (133 mg, 38.9%). MS (ESI): m/z=291.3[M+H]⁺.

BB7a and BB7b 4-Nitrophenyl(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate(BB7a) and 4-nitrophenyl(4aS,8aR)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate(BB7b)

To a suspension ofrac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;dihydrochloride salt (4.5 g, 19.6 mmol, BB1) in dry DCM (125 mL) at 0°C. was added DIPEA (6.35 g, 8.58 mL, 49.1 mmol) followed by4-nitrophenyl carbonochloridate (4.35 g, 21.6 mmol). The reactionmixture was stirred at 0° C. for 10 min and at RT for 2 h. The crudereaction was diluted with DCM and transferred into a separating funnelfor extraction with sat. aq. Na₂CO₃ solution. The organic phase wascollected and the aqueous phase was back-extracted with DCM. Thecombined organic phases were dried over Na₂SO₄ and evaporated down todryness to yield 6.62 g of a crude racemic product (BB7) as a yellowsolid. The crude material was directly submitted for a chiral SFCseparation to yield enantiomer BB7b (2.72 g, second eluting enantiomer)as a yellow solid and enantiomer BB7a (3.25 g, first eluting enantiomer)as a light beige solid but contaminated with BB7b. A further SFC chiralseparation was carried out to yield 2.71 g of BB7a. MS (ESI): m/z=322.2[M+H]⁺ for both enantiomers.

BB8 5-tert-Butyl-2-(4-piperidylmethyl)oxazole; hydrochloride salt

A solution of tert-butyl4-[(5-tert-butyloxazol-2-yl)methyl]piperidine-1-carboxylate (167 mg, 518μmol) in HCl 2M in diethyl ether (2.59 mL, 5.18 mmol) was stirred at RTfor 5 h before another 1.29 mL (2.59 mmol) of HCl 2M in diethyl etherwas added. The white suspension was stirred at RT overnight. The mixturewas cooled down in an ice-bath, then filtered and washed with diethylether to get the desired compound as a colorless solid (0.126 g, 94.0%).MS (ESI): m/z=223.2 [M+H]⁺.

Step a) (5-tert-Butyloxazol-2-yl)methyl-triphenyl-phosphonium bromide

To a solution of 2-(bromomethyl)-5-(tert-butyl)oxazole (600 mg, 2.75mmol, CAS RN 1334492-54-4) in diethyl ether (5 mL) was addedtriphenylphosphine (722 mg, 2.75 mmol, CAS RN 603-35-0) and the mixturewas stirred at RT for 64 h. The suspension was cooled down in anice-bath and then filtered. The filter cake was washed a small volume ofcold diethyl ether to give the desired compound as a light yellow solid(0.864 g, 65.4%). MS (ESI): m/z=400.2 [M−Br+H]⁺.

Step b) tert-Butyl4-[(5-tert-butyloxazol-2-yl)methylene]piperidine-1-carboxylate

To an ice-cold suspension of(5-tert-butyloxazol-2-yl)methyl-triphenyl-phosphonium bromide (355 mg,739 μmol) in THF (7 mL) was added potassium tert-butylate 1M solution inTHF (738 μL, 738 μmol) and the reaction stirred at this temperature for15 min. Then, tert-butyl 4-oxopiperidine-1-carboxylate (162 mg, 813μmol, CAS RN 79099-07-3) was added to the turbid, orange solution andstirring was continued at 0° C. for another 15 min., then at RT for 42h. The reaction mixture was poured on half-saturated aqueous NH₄Clsolution and EtOAc and the layers were separated. The aqueous layer wasextracted twice with EtOAc. The combined organic layers were dried overMgSO₄, filtered, treated with silica gel and evaporated. The compoundwas purified by silica gel chromatography on a 12 g column using an MPLCsystem eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50) toprovide the desired compound as a colorless solid (0.180 mg; 76.0%). MS(ESI): m/z=321.3 [M+H]⁺.

Step c) tert-Butyl4-[(5-tert-butyloxazol-2-yl)methyl]piperidine-1-carboxylate

To a solution of tert-butyl4-[(5-tert-butyloxazol-2-yl)methylene]piperidine-1-carboxylate (180 mg,562 μmol) in MeOH (1 mL) and EtOAc (1 mL) was added Pd/C 10% (17.9 mg,16.9 μmol) and the suspension was stirred under a hydrogen atmosphere at1.3 bar for 2 h. The suspension was filtered over a microfilter and thefiltrate was evaporated to get the desired compound as a colorless oil(0.167 g; 92.2%). MS (ESI): m/z=323.3 [M+H]⁺.

BB12 4-[(2-Chloro-4-fluoro-phenoxy)methyl]-4-methyl-piperidine;Hydrochloride Salt

To a solution of tert-butyl4-[(2-chloro-4-fluoro-phenoxy)methyl]-4-methyl-piperidine-1-carboxylate(186 mg, 0.520 mmol) in EtOAc (1.5 mL) was added HCl in EtOAc (4 M, 1.5mL) at 0° C. The solution was stirred at 15° C. for 3 h. The solutionwas concentrated under vacuum, then dried by lyophilization to givedesired product as a white solid (64.0 mg, 0.220 mmol, 40.3% yield). MS(ESI): m/z=258 [M+H]⁺.

Step a) tert-Butyl4-methyl-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate

To a solution of tert-butyl4-(hydroxymethyl)-4-methyl-piperidine-1-carboxylate (500 mg, 2.14 mmol,CAS RN: 614730-97-1) in DCM (5 mL) was added NEt₃ (0.45 mL, 3.22 mmol)and methanesulfonyl chloride (0.23 mL, 3.0 mmol) at 0° C. The mixturewas stirred at 0° C. for 2 h. The mixture was washed twice with water (3mL each) at 0° C., and dried over Na₂SO₄. The organic layer wasconcentrated in vacuum to yield the desired compound as colorless oil(766 mg, 2.46 mmol, 98.5%) which was used in the next step withoutfurther purification. MS (ESI): m/z=256 [M−56+H]⁺.

Step b) tert-Butyl4-[(2-chloro-4-fluoro-phenoxy)methyl]-4-methyl-piperidine-1-carboxylate

To a solution of tert-butyl4-methyl-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate (450 mg,1.46 mmol) in DMF (5 mL) was added Cs₂CO₃ (620 mg, 1.9 mmol) and2-chloro-4-fluorophenol (0.14 mL, 1.46 mmol) at 15° C. The mixture washeated to 90° C. and stirred for 16 h. The reaction solution was dilutedby EtOAc (10 mL), washed twice with brine (10 mL each), and dried overNa₂SO₄. The organic layer was concentrated under vacuum to give thecrude product (0.7 g) as light yellow oil. The crude product waspurified by prep-HPLC and dried by lyophilization to give the desiredcompound as colorless solid (186 mg, 0.520 mmol, 35.5% yield). MS (ESI):m/z=302 [M−56+H]⁺.

BB15 4-[(2-Chloro-4-fluoro-phenoxy)methyl]-4-fluoro-piperidine;Hydrochloride Salt

To a solution of tert-butyl4-[(2-chloro-4-fluoro-phenoxy)methyl]-4-fluoro-piperidine-1-carboxylate(220 mg, 0.610 mmol) in EtOAc (2 mL) was added HCl/EtOAc (0.4 mL, 3.6mmol) at 0° C. The solution was stirred at 15° C. for 2.5 h. Thesolution was concentrated in vacuo, then dried by lyophilization to givedesired product as a white solid (136.7 mg, 75.4%).

Step a) tert-Butyl4-fluoro-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate

To a solution of tert-butyl4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (500 mg, 2.14 mmol)in DCM (5 mL) was added NEt₃ (0.45 mL, 3.22 mmol) and methanesulfonylchloride (0.23 mL, 3 mmol) at 0° C. The mixture was stirred at 0° C. for2 h. The mixture was washed twice with H₂O (3 mL each) at 0° C., anddried over Na₂SO4. The organic layer was concentrated to provide thecompound as a colorless oil (766 mg, 98.5%) which was used in next stepwithout further purification. MS (ESI): m/z=256 [M−56+H]⁺.

Step b) tert-Butyl4-[(2-chloro-4-fluoro-phenoxy)methyl]-4-fluoro-piperidine-1-carboxylate

To a solution of tert-butyl4-fluoro-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate (383 mg,1.23 mmol) in DMF (4 mL) was added Cs₂CO₃ (601 mg, 1.85 mmol),2-chloro-4-fluorophenol (0.13 mL, 1.35 mmol) and 2-chloro-4-fluorophenol(0.13 mL, 1.35 mmol) at 15° C. The mixture was heated to 85° C. andstirred for 16 h. The mixture was extracted three times with EtOAc (5 mLeach) at 15° C., the combined organic layers washed three times withbrine (5 mL each), dried over Na₂SO₄, filtered and evaporated. The crudeproduct was purified by preparative HPLC and dried by lyophilization togive the desired compound as light yellow oil (275 mg, 0.760 mmol,61.5%). MS (ESI): m/z=306 [M−56+H]⁺.

BB16rac-(4aR,8aS)-6-(4-(Hydroxymethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

To a suspension ofrac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;dihydrochloride salt (450 mg, 1.96 mmol, BB1) in dry DMF (9 mL) cooleddown to 0° C. under an inert atmosphere was added DIPEA (787 mg, 1.06mL, 6.09 mmol) and 4-nitrophenyl carbonochloridate (475 mg, 2.36 mmol).The reaction mixture was stirred at 0° C. for 30 min.Piperidin-4-ylmethanol (271 mg, 2.36 mmol, CAS RN 6457-49-4) and DIPEA(381 mg, 515 μL, 2.95 mmol) were added, and the reaction mixture wasstirred at 100° C. for 14 h. Volatiles were removed in vacuo and thecrude residue was purified by flash chromatography with a 24 g SiO₂column using an eluent mixture of DCM and MeOH (5% to 25%). The crudeproduct was submitted for SFC purification to yield the desired compoundas a light yellow oil (338 mg). MS (ESI): m/z=298.3 [M+H]⁺.

BB17 4,4-Difluoro-1-(piperidin-4-ylmethyl)piperidine; DihydrochlorideSalt

To a solution of tert-butyl4-((4,4-difluoropiperidin-1-yl)methyl)piperidine-1-carboxylate (453 mg,1.07 mmol) in dioxane (2.5 mL) was added HCl (4.0M solution in dioxane)(2.67 mL, 10.7 mmol) and the reaction mixture was stirred at roomtemperature for 14 h. Volatiles were removed in vacuo to yield thedesired compound as a white solid (286 mg) which was used in the nextstep without further purification. MS (ESI): m/z=219.3 [M+H]⁺.

Step a) tert-Butyl4-((4,4-difluoropiperidin-1-yl)methyl)piperidine-1-carboxylate

To a solution of a tert-butyl 4-(bromomethyl)piperidine-1-carboxylate(0.5 g, 1.8 mmol, CAS RN: 158407-04-6) in dry DMF (4 mL) was added4,4-difluoropiperidine; dihydrochloride salt (425 mg, 2.7 mmol) andCs₂CO₃ (1.17 g, 3.59 mmol). The reaction mixture was then stirred at 80°C. under microwave radiation for 60 min. Insolubles were removed byfiltration, the filtrate was then concentrated in vacuo, and theobtained crude residue was suspended in DCM and filtered through a padof Celite to give a crude yellow oil, which was purified by flashchromatography on a SiO₂ column, using an eluent mixture of n-heptaneand EtOAc (10% to 60%) to yield the desired product as a colorless oil(453 mg). The compound was carried forwards to the next step withoutfurther purification. MS (ESI): m/z=319.3 [M+H]⁺.

BB19N-(azetidin-3-ylmethyl)-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethan-1-amine;bis(trifluoroacetate) salt

To a solution of tert-butyl3-(((2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carboxylate(1 g, 2.42 mmol) in DCM (10 mL) was added TFA (5.53 g, 3.74 mL, 48.5mmol). The resulting reaction mixture was stirred at RT for 1 h. Thereaction mixture was concentrated in vacuo to yield the desired compoundas colorless oil (1.29 g). MS (ESI): m/z=313.5 [M+H]⁺.

Step a) tert-Butyl3-(((2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carboxylate

To a dry flask with septum was added under nitrogen tert-butyl3-(aminomethyl)azetidine-1-carboxylate (0.852 g, 4.57 mmol),triethylamine (1.39 g, 1.91 mL, 13.7 mmol),2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethan-1-one (1.11 g, 780μL, 4.57 mmol), and dry DCM (28 mL). Titanium tetrachloride 1 M in DCM(2.29 mL, 2.29 mmol) was added via a syringe to the ice-cooled flask(exothermic). The reaction was stirred overnight at RT, then carefullyquenched with a solution of NaCNBH₃ (862 mg, 13.7 mmol) in MeOH (8.79 g,11.1 mL, 274 mmol) and stirred overnight. The reaction was basified withsat. NaHCO₃ solution. The obtained insoluble material was filtered offover celite. Extraction of the filtrate with DCM, the organic layerswere combined, washed with brine, dried over Na₂SO₄ and concentrated.The crude material was purified by flash chromatography (silica gel, 50g, 0% to 50% EtOAc in n-heptane to yield tert-butyl3-(((2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carboxylatewhich was used in the next step without further purification.

BB26 3-Chloro-4-(4-piperidylmethoxy)benzonitrile; Hydrochloride Salt

To a solution of tert-butyl4-[(2-chloro-4-cyano-phenoxy)methyl]piperidine-1-carboxylate (300 mg,0.860 mmol) in EtOAc (3 mL) was added HCl in EtOAc (4M, 2.0 mL) at 0° C.The solution was stirred at 15° C. for 3 h. The solution wasconcentrated in vacuo, then dried by lyophilization to give desiredproduct as a white solid (238 mg, 0.830 mmol, 96% yield). MS (ESI):m/z=251 [M+H]⁺.

Step a) tert-Butyl4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

To a solution of N-Boc-4-piperidinemethanol (10.0 g, 46.5 mmol, 1 eq) inDCM (200 mL) was added NEt₃ (7.04 g, 69.7 mmol), then methanesulfonylchloride (3.95 mL, 51.1 mmol) was added at 0° C. and the mixture wasstirred at 0° C. for 1 h. The mixture was poured into ice-water, theaqueous phase was extracted twice with DCM (50 mL each). The combinedorganic layers were washed with brine (50 mL), and concentrated undervacuum. The residue was directly used without any purification. MS(ESI): m/z=238.1 [M+H]⁺.

Step b) tert-Butyl4-[(2-chloro-4-cyano-phenoxy)methyl]piperidine-1-carboxylate

To a solution of tert-butyl4-(methylsulfonyloxymethyl)piperidine-1-carboxylate (700 mg, 2.39 mmol)in DMF (7 mL) was added Cs₂CO₃ (855 mg, 2.62 mmol) and3-chloro-4-hydroxybenzonitrile (0.25 mL, 2.39 mmol) at 15° C. Themixture was heated to 85° C. and stirred for 16 h. The reaction mixturewas diluted with EtOAc (8 mL) at 15° C., washed three times with brine(8 mL each), the combined organic layers were dried over Na₂SO₄ andevaporated. The colorless residue (0.75 g) was purified by prep-HPLC anddried by lyophilization to give the desired product as a white solid(531 mg, 1.51 mmol, 53.4%). MS (ESI): m/z=295 [M−56+H]⁺.

BB27 4-((4-(Trifluoromethyl)-1H-imidazol-1-yl)methyl)piperidine;Hydrochloride Salt

To a solution of tert-butyl4-((4-(trifluoromethyl)-1H-imidazol-1-yl)methyl)piperidine-1-carboxylate(430 mg, 1.29 mmol) in dioxane (3 mL) was added HCl (4 M solution indioxane; 3.22 mL, 12.9 mmol) and the reaction mixture was stirred at RTfor 14 h. Volatiles were removed in vacuo to give the crude product (362mg) which was used in the next step without further purification. MS(ESI): m/z=234.2 [M+H]⁺.

Step a) tert-Butyl4-((4-(trifluoromethyl)-1H-imidazol-1-yl)methyl)piperidine-1-carboxylate

To a solution of a tert-butyl 4-(bromomethyl)piperidine-1-carboxylate(0.5 g, 1.8 mmol, CAS RN: 158407-04-6) in dry DMF (4 mL) was added4-(trifluoromethyl)-1H-imidazole (293 mg, 2.16 mmol) and Cs₂CO₃ (1.17 g,3.59 mmol). The reaction mixture was then stirred at 80° C. for 14 h.Insolubles were removed by filtration, and the filtrate was concentratedin vacuo. The crude residue was suspended in DCM and filtered through apad of Celite to give a yellow oil, which was purified by flashchromatography with a SiO₂ column, using an eluent mixture of n-heptaneand EtOAc (10% to 90%). This yielded the first fraction (301 mg) of thedesired product as a colorless oil, and a second fraction (261 mg) of amixture of the desired product with impurities. The second fraction wassubmitted for SFC purification, and the purified product was combinedwith the first fraction to yield 430 mg of the desired product as acolorless oil. MS (ESI): m/z=334.2 [M+H]⁺.

BB29 3-((2-Chloro-4-(trifluoromethyl)phenoxy)methyl)azetidine

Trifluoroacetic acid (2 g, 1.35 mL, 17.5 mmol) was added to a solutionof tert-butyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)azetidine-1-carboxylate(320 mg, 875 μmol) in DCM (4.37 mL) and the solution was stirred at RTfor 2 h. The solvent was removed under reduced pressure and theresulting pale oil (470 mg) was diluted with EtOAc and washed with aq.Na₂CO₃ solution. The aqueous phase was extracted three times with EtOAc,and the combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to afford the compound asa yellow oil (259 mg, 877 μmol). MS (ESI): m/z=266.1 [M+H]⁺.

Step a) tert-Butyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)azetidine-1-carboxylate

To a solution of 2-chloro-4-(trifluoromethyl)phenol (525 mg, 357 μL,2.67 mmol), tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (500 mg,2.67 mmol, CAS RN: 142253-56-3) and triphenylphosphine (770 mg, 2.94mmol) in DCM (13.4 mL) was added DIAD (594 mg, 571 μL, 2.94 mmol)dropwise and the reaction was stirred at RT for 17 h. The reactionmixture was quenched by addition of sat. aq. NaHCO₃ solution (20 mL).The phases were separated and the aq. phase was extracted with DCMtwice. The combined organic layers were dried over Na₂SO₄ andconcentrated to dryness. The residue was dissolved in EtOH (7 mL) and ahomogeneous solution of zinc chloride (218 mg, 1.6 mmol) in EtOH (2 mL,0.5 M) was added. The mixture was stirred for 30 min during which awhite solid precipitated. The white solid was filtered off and washedwith EtOH. The filtrate was concentrated to give a yellow oil with awhite precipitate. The crude was immobilized on Isolute and purified bycolumn chromatography (40 g, 0 to 30% EtOAc in heptanes) to afford thetitle compound as a white solid (764.6 mg, 1.99 mmol, 74.4%). MS (ESI):m/z=310.1[M−56+H]⁺.

BB30 N-benzyl-N-(2-hydroxyethyl)piperidine-4-carboxamide hydrochloride

To a solution of tert-butyl4-(benzyl(2-hydroxyethyl)carbamoyl)piperidine-1-carboxylate (0.080 g,221 μmol) in DCM (1 mL) was added HCl 2 M in diethyl ether (1.1 mL, 2.21mmol). The resultant reaction mixture was stirred at RT for 1 h and thenconcentrated under vacuum at 22° C. to yield the desired compound as acolorless oil (63 mg) (BB30). MS (ESI): m/z=263.18 [M+H]⁺.

Step a) tert-Butyl4-(benzyl(2-hydroxyethyl)carbamoyl)piperidine-1-carboxylate

In a 10 mL glastube, to 1-(tert-butoxycarbonyl)piperidine-4-carboxylicacid (0.1 g, 436 μmol) in DMF (2 mL) was added 2-(benzylamino)ethan-1-ol(72.5 mg, 480 μmol), DIPEA (169 mg, 229 μL, 1.31 mmol) and HATU (182 mg,480 μmol), stirred at RT for 1 h and extracted with H₂O/DCM. The crudematerial was purified by flash chromatography (silica gel, 20 g, 50% to100% EtOAc in n-heptane) to yield the compound as a light yellow oil(156 mg).

BB31 N-benzylpiperidine-4-carboxamide hydrochloride

tert-Butyl 4-(benzylcarbamoyl)piperidine-1-carboxylate (0.138 g, 433μmol) was dissolved in DCM (1 mL) and HCl 2M in diethyl ether (2.17 mL,4.33 mmol) was added. The reaction mixture was stirred for 2 h. Theresidue was concentrated in vacuo to yield the compound (108 mg) as acolorless oil. MS (ESI): m/z=219.15 [M+H]⁺.

Step a) tert-Butyl 4-(benzylcarbamoyl)piperidine-1-carboxylate

In a 10 mL glastube, to 1-(tert-butoxycarbonyl)piperidine-4-carboxylicacid (0.1 g, 436 μmol) in DMF (2 mL) was added phenylmethanamine (51.4mg, 52.4 μL, 480 μmol), DIPEA (169 mg, 229 μL, 1.31 mmol) and HATU (182mg, 480 μmol), stirred at RT for 2 h and extracted with H₂O/DCM. Thecrude material was purified by flash chromatography (silica gel, 20 g,50% to 100% EtOAc in n-heptane) to yield the compound as a colorless oil(0.138 g).

BB32 4-((4-(tert-Butyl)-1H-pyrazol-1-yl)methyl)piperidine; HydrochlorideSalt

To a solution of tert-butyl4-((4-(tert-butyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (100mg, 311 μmol) in dioxane (1 mL) was added HCl (4.0M solution in dioxane;1.17 mL, 4.67 mmol) and the reaction mixture was stirred at RT for 14 h.Volatiles were removed in vacuo to give 84 mg of a crude product whichwas used in the next step without further purification. MS (ESI):m/z=222.3 [M+H]⁺.

Step a) tert-Butyl4-((4-(tert-butyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

To a solution of a tert-butyl 4-(bromomethyl)piperidine-1-carboxylate(0.5 g, 1.8 mmol, CAS RN 158407-04-6) in dry DMF (4 mL) was added4-(tert-butyl)-1H-pyrazole (268 mg, 2.16 mmol) and NaH (86.3 mg, 2.16mmol). The reaction mixture was stirred at 80° C. for 14 h. The reactionwas quenched by addition of few drops of sat. aq. NH₄Cl solution, andtransferred into a separating funnel for partitioning between DCM andsat. aq. NaHCO₃ solution. The organic phase was collected and theaqueous phase was back-extracted with DCM. The combined organic phaseswere dried over Na₂SO₄ and evaporated down to dryness. The crudematerial was purified by flash chromatography with a SiO₂ column,eluting with a mixture of n-heptane and EtOAc (5% to 60%) to yield thedesired compound as a colorless oil (102 mg). MS (ESI): m/z=322.3[M+H]⁺.

BB33(2R,4aR,8aS)-2-methyl-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one

To a solution of6-benzyl-2-methyl-5,6,7,8-tetrahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one(Isomer A, 1.10 g, 4.26 mmol) in EtOAc (16 mL) and MeOH (16 mL) wasadded under argon Pd—C (227 mg, 213 μmol) and the suspension was stirredunder a hydrogen atmosphere (balloon) at 1 bar for 24 h. The suspensionwas filtered over a microglass filter and washed with 20 mL EtOAc underinert gas. The filtrate was evaporated to give BB33 as a colorless solid(715 mg). MS (ESI): m/z=170.8 [M+H]⁺. Note: Only the single enantiomerformed during the reduction.

Step a) 2-Methyl-4H-pyrido[4,3-b][1,4]oxazin-3-one

To a solution of 3-aminopyridin-4-ol (2.5 g, 22.7 mmol) in DMF (100 mL)was added dropwise 2-chloropropanoyl chloride (3.03 g, 2.31 mL, 23.8mmol) and the mixture was stirred at RT for 30 min. After addition ofK₂CO₃ (7.84 g, 56.8 mmol), the suspension was heated to 100° C. (oilbath) for 20 h. The DMF was removed in vacuo, then 100 mL EtOAc wereadded and stirred at RT for 10 min, and it was washed with 50 mL H₂O,extracted 3 times with EtOAc. The organic phases were combined, driedwith MgSO₄ and concentrated under vacuo to yield 3.72 g of2-methyl-4H-pyrido[4,3-b][1,4]oxazin-3-one which was used in the nextstep without further purification.

Step b)6-Benzyl-2-methyl-3-oxo-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-6-iumbromide

A suspension of 2-methyl-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (3.72 g,22.7 mmol) in DCM (32 mL) and MeOH (8 mL) was treated with(bromomethyl)benzene (4.65 g, 3.23 mL, 27.2 mmol) and the mixture wasstirred at RT for 60 h. A suspension formed, which was cooled down to 0°C., 20 mL n-hexane were added and then the precipitate was filtered. Theresidue was washed with 15 mL of cold DCM/n-hexan to yield the compoundas an off-white solid (5.2 g). MS (ESI): m/z=255 [M+H]⁺.

Step c)6-Benzyl-2-methyl-5,6,7,8-tetrahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

To a suspension of6-benzyl-2-methyl-3-oxo-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-6-iumbromide (5.2 g, 15.5 mmol) in EtOH (38 mL) was added in portions NaBH₄(763 mg, 20.2 mmol) (exothermic, 22° C. to 30° C., yellow suspension).After the exothermic reaction faded out the mixture was stirred at roomtemperature for 3 h, then at 60° C. for 1 h and at 22° C. for 1 h. Thereaction mixture was evaporated, partitioned between H₂O and EtOAc andthe layers were separated. The aqueous layer was extracted once withEtOAc. The organic layers were washed twice with H₂O, dried over MgSO₄,filtered, treated with silica gel and evaporated. The compound waspurified by silica gel chromatography on a 120 g column using an MPLCsystem eluting with a gradient of n-heptane:EtOAc (50 to 100 in 30 min.)to provide the compound as a light yellow solid (2.48 g) which could beused in the following step without further purification.

Step d)6-Benzyl-2-methyl-5,6,7,8-tetrahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

The enantiomers were separated by preparative chiral HPLC (Chiralcel ODcolumn) using an isocratic mixture of EtOH (containing 0.05% ofNH4OAc):n-heptane (10:90). The fractions were evaporated to provide thedesired compounds as light yellow solids (Isomer A 1.17 g, Isomer B 1.10g).

BB34N-(azetidin-3-ylmethyl)-2,2,2-trifluoro-1-(3-(trifluoromethyl)phenyl)ethan-1-amine

In a 100 mL two-necked flask, benzyl3-(((2,2,2-trifluoro-1-(3-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carboxylate(0.913 g, 2.05 mmol) was dissolved in a mixture of THF (5 mL) and MeOH(5 mL). Pd/C 10% (109 mg, 102 μmol) was added under argon. The flask waspurged and backfilled with H₂ gas (3 times). The reaction mixture wasthen stirred at 25° C. for 4 h. The suspension was filtered overdecalite, concentrated and the resulting title compound (611 mg,colorless oil) used directly for the next step. MS (ESI): m/z=313.4[M+H]⁺.

Step a) Benzyl3-(((2,2,2-trifluoro-1-(3-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carboxylate

To a dry flask with septum was added benzyl3-(aminomethyl)azetidine-1-carboxylate (0.5 g, 2.27 mmol), NEt₃ (689 mg,949 μL, 6.81 mmol),2,2,2-trifluoro-1-(3-(trifluoromethyl)phenyl)ethan-1-one (554 mg, 391μL, 2.27 mmol), and dry DCM (15 mL). Titanium tetrachloride 1M in DCM(1.13 mL, 1.13 mmol) was added via a syringe and the flask was cooled inan ice bath (exothermic). The reaction was stirred at RT overnight,carefully quenched with a solution of NaCNBH₃ (428 mg, 6.81 mmol) inMeOH (4.36 g, 5.51 mL, 136 mmol) and acetic acid (0.1 mL) and stirred atRT overnight. The reaction was basified with sat. aq. NaHCO₃ solutionand the insoluble material obtained was filtered away over celite. Thefiltrate was extracted with DCM. The organic layers were combined,washed with brine, dried over Na₂SO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography (silica gel, 50 g,0% to 50% EtOAc in n-heptane) to yield the desired compound as acolorless oil (913 mg). MS (ESI): m/z=447.2 [M+H]⁺.

BB35N-(azetidin-3-ylmethyl)-1-(2,4-dichlorophenyl)-2,2,2-trifluoroethan-1-amine

In a 100 mL two-necked flask, benzyl3-(((1-(2,4-dichlorophenyl)-2,2,2-trifluoroethyl)amino)methyl)azetidine-1-carboxylate(0.660 g, 1.48 mmol) was dissolved in EtOAc (20 mL) to give a colorlesssolution. Pd/C 10% (78.5 mg, 73.8 μmol) was added under argon. The flaskwas purged and backfilled with H₂ gas (3 times). The reaction mixturewas stirred at 25° C. for 4 h. LC-MS showed a mixture of the titleproductN-(azetidin-3-ylmethyl)-1-(2,4-dichlorophenyl)-2,2,2-trifluoroethan-1-aminetogether with the dehalogenated side-productsN-(azetidin-3-ylmethyl)-1-(2-chlorophenyl)-2,2,2-trifluoroethan-1-amineand N-(azetidin-3-ylmethyl)-1-phenyl-2,2,2-trifluoroethan-1-amine. Thereaction mixture was filtered over decalite, concentrated in vacuo andused directly for the next step.

Step a) Benzyl3-[[[1-(2,4-dichlorophenyl)-2,2,2-trifluoro-ethylidene]amino]methyl]azetidine-1-carboxylate

To a dry flask with septum was added under nitrogen benzyl3-(aminomethyl)azetidine-1-carboxylate (0.500 g, 2.27 mmol, CAS RN1016731-24-0), NEt₃ (689 mg, 949 μL, 6.81 mmol),1-(2,4-dichlorophenyl)-2,2,2-trifluoroethan-1-one (556 mg, 2.27 mmol,and dry DCM (16.4 mL). Titanium tetrachloride (1 M solution in DCM; 1.13mL, 1.13 mmol) was added via a syringe to the ice-cooled flask(exothermic). The reaction was stirred at RT overnight, carefullyquenched with a solution of NaCNBH₃ (428 mg, 6.81 mmol) in MeOH (4.36 g,5.51 mL, 136 mmol) and stirred for 6 h. LCMS indicated the reactionstopped at the imine.

The reaction was basified with sat. NaHCO₃. The obtained insolublematerial was filtered over celite and the filtrate was extracted withDCM. The organic layers were combined, washed with brine, dried overNa₂SO₄ and concentrated. The crude material was purified by flashchromatography (silica gel, 50 g, 0% to 50% EtOAc in n-heptane) to givethe desired compound as a colorless oil (1 g).

Step b) Benzyl3-(((1-(2,4-dichlorophenyl)-2,2,2-trifluoroethyl)amino)methyl)azetidine-1-carboxylate

In a 25 mL two-necked flask, benzyl3-[[[1-(2,4-dichlorophenyl)-2,2,2-trifluoro-ethylidene]amino]methyl]azetidine-1-carboxylate(1 g, 2.25 mmol) was dissolved in THF (10 mL) and MeOH (1 mL) to give acolorless solution. Acetic acid (135 mg, 129 μL, 2.25 mmol) and NaCNBH₃(423 mg, 6.74 mmol) were added. The reaction mixture was stirred at 25°C. for 6 h. The reaction was basified with sat. NaHCO₃. The obtainedinsoluble material was filtered over celite and the filtrate wasextracted with DCM. The organic layers were combined, washed with brine,dried over Na₂SO₄ and concentrated. The crude material was purified byflash chromatography (silica gel, 50 g, 0% to 50% EtOAc in heptane) toafford the title compound as a colorless oil (660 mg) which used in thenext step without further purification.

BB36 cis-4-((2-Chloro-4-fluorophenoxy)methyl)-3-methylpiperidine;Hydrochloride Salt

tert-Butylcis-4-((2-chloro-4-fluorophenoxy)methyl)-3-methylpiperidine-1-carboxylate(115 mg, 321 μmol) was dissolved in DCM (2 mL) and 2M HCl in ether (161μL, 321 μmol) was added. The reaction was stirred at RT for 6 h, thenthe solvent was removed in vacuo. The crude product (94 mg, colorlessfoam) was used in the next step without purification. MS (ESI):m/z=258.2 [M+H]⁺.

Step a) tert-Butylcis-4-((2-chloro-4-fluorophenoxy)methyl)-3-methylpiperidine-1-carboxylate

Mitsunobu reaction: In a 50 mL four-necked sulphonation flask underargon, tert-butyl cis-4-(hydroxymethyl)-3-methylpiperidine-1-carboxylate(840 mg, 3.66 mmol) was dissolved in THF (15 mL),2-chloro-4-fluorophenol (590 mg, 439 μL, 4.03 mmol) andtriphenylphosphine (1.06 g, 4.03 mmol) were added. The clear solutionwas stirred 5 min at RT, then cooled to 0-2° C. and DEAD (702 mg, 638μL, 4.03 mmol) was added over 10 min. The reaction mixture was stirredat 2-4° C. for 1 h, then stirred over night at RT. 50 mL diethyletherwere added, the mixture was washed with 2 x 25 mL water, 3×20 mL 1 NNaOH, 1 x 20 mL brine, the organic phase was dried with Mg₂SO₄, afterremoving the solvent in vacuo 2.7 g yellow oil were obtained. To removethe triphenylphosphinoxide, the residue was stirred inn-Heptane/diethylether for 30 min, the solids was filtered away, thefiltrate was concentrated in vacuo, to obtain 1.8 g crude product thatwas purified by flash chromatography (silica gel, 50 g, 0% to 30% EtOAcin heptane, 40 min): tert-butylcis-4-((2-chloro-4-fluorophenoxy)methyl)-3-methylpiperidine-1-carboxylate,1.21 g white solid.

BB39 3-((2-Fluoro-4-(trifluoromethoxy)benzyl)oxy)azetidine;Trifluoroacetate Salt

To a solution of tert-butyl3-((2-fluoro-4-(trifluoromethoxy)benzyl)oxy)azetidine-1-carboxylate (415mg, 1.14 mmol) in DCM (5 mL) was added TFA (1.3 g, 875 μL, 11.4 mmol)and the reaction mixture was stirred at RT for 3 h. Volatiles wereremoved in vacuo to yield 455 mg of a light yellow oil that was used inthe next step without further purification. MS (ESI): m/z=266.1 [M+H]⁺.

Step a) tert-Butyl3-((2-fluoro-4-(trifluoromethoxy)benzyl)oxy)azetidine-1-carboxylate

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (200 mg,1.15 mmol) in dry THF (5 mL) was added potassium tert-butoxide (1.65 Msolution in THF, 735 μL, 1.21 mmol) and the reaction mixture was stirredat RT for 15 min followed by addition of1-(bromomethyl)-2-fluoro-4-(trifluoromethoxy)benzene (315 mg, 1.15mmol). The reaction mixture was then stirred at room temperature for 14h. The crude reaction was diluted with EtOAc and extracted with aq. 1 MNaHCO₃ solution, the organic phase was collected and the aqueous phasewas back-extracted with EtOAc. The combined organic phases were driedover NaSO₄ and evaporated down to dryness to yield 418 mg of the crudeproduct which was used in the next step without further purification. MS(ESI): m/z=310.1 [M−56+H]⁺.

BB40 N-(azetidin-3-yl)-2-chloro-4-fluoro-benzamide; TrifluoroacetateSalt

To a solution of tert-butyl3-[(2-chloro-4-fluoro-benzoyl)amino]azetidine-1-carboxylate (346 mg,1.05 mmol) in DCM (3.5 mL) was added TFA (0.7 mL) at 0° C. The solutionwas stirred at 0° C. for 2 h. The reaction was concentrated in vacuum togive the crude product (600 mg) as light yellow oil. The crude productwas purified by prep-HPLC (0.1% TFA in H₂O and MeCN) and dried bylyophilization to give desired compound as colorless solid (223 mg,0.650 mmol, 59.2% yield). MS (ESI): m/z=229 [M+H]⁺.

Step a) tert-Butyl3-[(2-chloro-4-fluoro-benzoyl)amino]azetidine-1-carboxylate

To a solution of 2-chloro-4-fluorobenzoic acid (500 mg, 2.86 mmol),1-Boc-3-(amino)azetidine (493 mg, 2.86 mmol) and DMAP (35.0 mg, 0.290mmol) in THF (10 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (714 mg,3.72 mmol) at 0° C. The mixture was heated to 30° C. and stirred for 16h. The reaction was diluted with EtOAc (5 mL), washed three times withbrine (10 mL each) and dried over Na₂SO₄. The organic layer wasconcentrated in vacuum to give the crude product (0.72 g) as yellow oil.The crude product was purified by prep-HPLC and dried by lyophilizationto give desired compound as a colorless solid (546 mg, 1.66 mmol, 57.9%yield). MS (ESI): m/z=273 [M−56+H]⁺.

BB41N-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-methyl-1-[4-(trifluoromethyl)phenyl]ethanamine;Trifluoroacetate Salt

To a solution of tert-butyl3-((methyl(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carboxylate(0.256 g, 600 μmol) in DCM (5 mL) was added TFA (1.37 g, 925 μL, 12mmol). The resulting reaction mixture was stirred at RT for 1 h. Thereaction mixture was concentrated in vacuo to provide the desiredcompound as a colorless oil (268 mg). MS (ESI): m/z=327.4 [M+H]⁺.

Step a) tert-Butyl3-((methyl(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carboxylate

To a dry flask with septum and 3 Å molecular sieves was added undernitrogen tert-butyl 3-((methylamino)methyl)azetidine-1-carboxylate(0.300 g, 293 μL, 1.5 mmol), TEA (455 mg, 626 μL, 4.49 mmol),2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethan-1-one (363 mg, 255μL, 1.5 mmol), and dry DCM (9.86 mL). Titanium tetrachloride 1 M in DCM(749 μL, 749 μmol) was added via a syringe to the ice-cooled flask(exothermic). The reaction was stirred at RT overnight, carefullyquenched with a solution of NaCNBH₃ (282 mg, 4.49 mmol) in MeOH (3.64mL, 89.9 mmol) and stirred at RT for 2 h. The reaction was basified withsat. NaHCO₃ solution. The obtained insoluble material was filtered overcelite and the filtrate was extracted with DCM. The organic layers werecombined, washed with brine, dried over Na₂SO₄ and concentrated. Thecrude material was purified by flash chromatography (silica gel, 50 g,0% to 50% EtOAc in n-heptane) and was used directly for the next step.

BB42N-methyl-N-(piperidin-4-yl)-1-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamidehydrochloride

To a solution of tert-butyl4-(N-methyl-1-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)piperidine-1-carboxylate(0.301 g, 706 μmol) in DCM (2 mL) was added HCl 2M in diethyl ether(3.53 mL, 7.06 mmol). The resulting reaction mixture was stirred at RTovernight and then concentrated under vacuum at 22° C. to give 256 mg ofBB42 as off white solid, MS (ESI): m/z=327.2 [M+H]⁺

Step a) tert-butyl4-(N-methyl-1-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)piperidine-1-carboxylate

In a 20 mL glastube, to1-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic acid (177 mg, 770μmol) in DMF (5 mL) was added HATU (293 mg, 770 μmol) and DIPEA (271 mg,367 μL, 2.1 mmol). The reaction mixture was stirred for 15 min and thentert-butyl 4-(methylamino)piperidine-1-carboxylate (0.15 g, 700 μmol)was added. The reaction mixture was stirred at RT for 2 hours. Thereaction mixture was extracted with Water/DCM. The crude material waspurified by flash chromatography (silica gel, 20 g, 0% to 100% EtOAc inheptane) to yield the desired compound as a light yellow oil (301 mg).MS (ESI): m/z=371.2 [M−56+H]⁺

BB432-(2-chloro-3-(trifluoromethyl)phenyl)-N-methyl-N-(piperidin-4-yl)acetamide;hydrochloride salt

To a solution of tert-butyl4-(2-(2-chloro-3-(trifluoromethyl)phenyl)-N-methylacetamido)piperidine-1-carboxylate(0.301 g, 692 μmol) in DCM (2 mL) was added HCl (3.46 mL, 6.92 mmol).The resulting reaction mixture was stirred at RT for 2 days and thenconcentrated under vacuum at 22° C. to yield 252 mg of BB43 as off whitesolid. MS (ESI): m/z=335.1 [M+H]⁺.

Step a) tert-butyl4-(2-(2-chloro-3-(trifluoromethyl)phenyl)-N-methylacetamido)piperidine-1-carboxylate

In a 20 mL glass tube, to 2-(2-chloro-3-(trifluoromethyl)phenyl)aceticacid (184 mg, 770 μmol) in DMF (5 mL) was added HATU (293 mg, 770 μmol),DIPEA (271 mg, 367 μL, 2.1 mmol). The reaction mixture was stirred for15 min and then tert-butyl 4-(methylamino)piperidine-1-carboxylate(0.150 g, 700 μmol) was added. The reaction mixture was stirred at RTfor 2 hours, and then extracted with Water/DCM. The crude material waspurified by flash chromatography (silica gel, 20 g, 0% to 100% EtOAc inheptane) to yield tert-butyl4-(2-(2-chloro-3-(trifluoromethyl)phenyl)-N-methylacetamido)piperidine-1-carboxylateas light yellow oil, 301 mg, MS (ESI): m/z=379.1 [M−56+H]⁺

BB442-(2-Chloro-5-(trifluoromethyl)phenyl)-N-methyl-N-(piperidin-4-yl)acetamide;Hydrochloride Salt

Synthesized from 2-(2-chloro-5-(trifluoromethyl)phenyl)acetic andtert-butyl 4-(methylamino)piperidine-1-carboxylate. See synthesis ofBB43 for details. MS (ESI): m/z=335.1 [M+H]⁺.

BB46 3-Methyl-5-(piperidin-4-ylmethoxy)-2-(trifluoromethyl)pyridine;Dihydrochloride Salt

In a 25 mL tube tert-butyl4-(((5-methyl-6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate(87 mg, 232 μmol) was dissolved in DCM (2 mL) and then HCl in ether 2M(697 μL, 1.39 mmol) was added, the reaction mixture was stirred 12 h atRT. The mixture was concentrated in vacuum, yielding 80 mg of BB46 as awhite solid. MS (ESI): m/z=275.2 [M+H]⁺.

Step a) tert-Butyl4-(((5-methyl-6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate

In a 5 mL tube, tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate(80.7 mg, 375 μmol) was dissolved in DMF (1.5 mL), then NaH in Oil 60%(18 mg, 450 μmol) was added at room temperature, the mixture was stirredfor 20 min, then 5-bromo-3-methyl-2-(trifluoromethyl)pyridine (90 mg, 60μL, 375 μmol) was added, and it was stirred for 2 hr at RT, yielding abrown solution. 10 mL sat. NH₄Cl were added, it was extracted withwater/ethyl acetate, dried over MgSO₄, the solvent was removed at 40°C./150 mbar. The crude product was purified by flash chromatography(silica gel, 20 g, 0 to 40% EtOAc in n-heptane, in 35 min) to yield 87mg of tert-butyl4-(((5-methyl-6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate.MS (ESI): m/z=319.2 [M−56+H]⁺

BB58N-(azetidin-3-ylmethyl)-2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine

In a 100 mL two-necked flask, benzyl3-(((1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)amino)methyl)azetidine-1-carboxylate(707 mg, 1.64 mmol) was combined with THF (5 mL) and MeOH (5 mL) to givea colorless solution. Pd/C 10% (87.3 mg, 82.1 μmol) was added underargon. The flask was purged and backfilled with H₂ (3 times). Thereaction mixture was stirred at 25° C. for 1 h. The reaction mixture wasfiltered over decalite, concentrated and used directly for the nextstep. Colorless oil (472 mg). MS (ESI): m/z=263.2 [M+H]⁺ (theortho-chlorine was lost during the hydrogenation).

Step a:) Benzyl3-(((1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)amino)methyl)azetidine-1-carboxylate

To a dry flask under a stream of nitrogen was added benzyl3-(aminomethyl)azetidine-1-carboxylate (0.5 g, 2.27 mmol), triethylamine(689 mg, 949 μL, 6.81 mmol),1-(2-chloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone (519 mg, 2.27mmol), and dry DCM (15 mL). Titanium tetrachloride 1M in DCM (1.13 mL,1.13 mmol) was added via a syringe to the ice-cooled flask (exothermic).The reaction was stirred overnight at RT, carefully quenched with amethanolic solution of sodium cyanoborohydride (428 mg, 6.81 mmol) inmethanol (4.36 g, 5.51 mL, 136 mmol)+Acetic Acid (0.1 mL) and stirredovernight at RT. The reaction was basified with sat. NaHCO₃. Theinsoluble material obtained was filtered away over celite, the filtratewas extracted with DCM, the organic layers were combined, washed withbrine, dried over Na₂SO₄ and concentrated. Purification: The crudematerial was purified by flash chromatography (silica gel, 50 g, 0% to50% EtOAc in heptane) to yield 707 mg of Benzyl3-(((1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)amino)methyl)azetidine-1-carboxylateas a colorless oil. MS (ESI): m/z=431.2 [M+H]⁺.

BB592,2,2-Trifluoro-1-(piperidin-4-yl)-N-(3-(trifluoromethyl)benzyl)ethan-1-amine;hydrochloride salt

To a solution of tert-butyl4-(2,2,2-trifluoro-1-((3-(trifluoromethyl)benzyl)amino)ethyl)piperidine-1-carboxylate(0.140 g, 318 μmol) in DCM (2 mL) was added HCl 2M in diethyl ether(1.59 mL, 3.18 mmol). The resulting reaction mixture was stirred at RTovernight and then concentrated under vacuum at 22° C. to yield 119 mgof the title compound as off-white solid. MS (ESI): m/z=340.8 [M+H]⁺.

Step a) tert-Butyl4-(2,2,2-trifluoro-1-((3-(trifluoromethyl)benzyl)amino)ethyl)piperidine-1-carboxylate

A solution of tert-butyl4-(1-amino-2,2,2-trifluoroethyl)piperidine-1-carboxylate (0.150 g, 531μmol) and 3-(trifluoromethyl)benzaldehyde (92.5 mg, 71.1 μL, 531 μmol)in 1,2-DCE (1 mL) was stirred for 1 hour at RT. Sodiumtriacetoxyborohydride (225 mg, 1.06 mmol) was then added at 0° C., andthe reaction mixture was stirred at RT overnight. The reaction mixturewas poured onto sat. NaHCO₃ and extracted with DCM. The organic layerswere combined, washed with brine, dried over Na₂SO₄ and concentrated invacuo. The crude material was purified by flash chromatography (silicagel, 20 g, 0% to 100% EtOAc in heptane) to yield 145 mg of the desiredcompound as a colorless oil. MS (ESI): m/z=383.1 [M−56+H]⁺

BB69 2-methyl-3-((4-(trifluoromethyl)benzyl)oxy)azetidine;Trifluoroacetate Salt

To a solution of tert-butyl2-methyl-3-((4-(trifluoromethyl)benzyl)oxy)azetidine-1-carboxylate (0.36g, 1.04 mmol) in DCM (4 mL) was added trifluoroacetic acid (1.19 g, 10.4mmol). The resulting reaction mixture was stirred at RT for 1 hour. Thereaction mixture was concentrated on high vacuum to yield BB69 as alight yellow oil, 399 mg, mixture of all four stereoisomers. MS (ESI):m/z=246.1 [M+H]⁺.

Step a) tert-Butyl2-methyl-3-((4-(trifluoromethyl)benzyl)oxy)azetidine-1-carboxylate

In a 25 mL two-necked flask,tert-butyl-3-hydroxy-2-methylazetidine-1-carboxylate (215 mg, 1.15 mmol)was dissolved in DMF (5 mL) to give a colorless solution. At 0° C.,sodium hydride (60% dispersion in mineral oil) (41.8 mg, 1.05 mmol) wasadded. The reaction mixture was stirred at 0° C. for 15 min. Then1-(bromomethyl)-4-(trifluoromethyl)benzene (0.250 g, 1.05 mmol) wasadded at 0° C. The reaction mixture was stirred at RT overnight. Thereaction mixture was poured onto 20 mL sat. NH₄Cl and extracted withEtOAc (2×50 mL). The organic layers were combined, washed with brine,dried over Na₂SO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography (silica gel, 20 g, 0% to 70% EtOAc inheptane) to yield 360 mg of tert-butyl2-methyl-3-((4-(trifluoromethyl)benzyl)oxy)azetidine-1-carboxylate as acolorless oil. MS (ESI): m/z=290.1 [M−56+H]⁺

BB87 3-Fluoro-5-(trifluoromethyl)benzyl 4-methylbenzenesulfonate

To a solution of (3-fluoro-5-(trifluoromethyl)phenyl)methanol (100 mg,72.5 L, 515 mol, Eq: 1) in DCM (2.58 mL) was added p-toluenesulfonicanhydride (185 mg, 567 mol), DIPEA (79.9 mg, 108 L, 618 μmol) and DMAP(6.29 mg, 51.5 mol). The reaction mixture was stirred for 4 h at 0° C.and for 2 days at room temperature. The reaction mixture was taken up inEtOAc and washed with water and brine. The organic layers were driedover MgSO₄ and concentrated in vacuo to give a yellow oil (178 mg) whichwas used without further purification.

In analogy to B39, and if not specified otherwise, the intermediatesshown in the following table were prepared from commercially availablebenzyl bromides or the prepared tosylate intermediates and thecorresponding tert-butyl 3-hydroxyazetidine-1-carboxylate buildingblocks.

BB No. Systematic Name Starting material MS, m/z BB37 3-((2-Chloro-4-1-(Bromomethyl)-2-chloro-4- 266.1 (trifluoromethyl)benzyl)oxy)azetidine;(trifluoromethyl)benzene [M + H]⁺ trifluoroacetate salt BB38 3-((4-1-(Bromomethyl)-4- 232.1 (Trifluoromethyl)benzyl)oxy)azetidine;(trifluoromethyl)benzene [M + H]⁺ trifluoroacetate salt BB453-((3-Methoxy-4- 4-(Bromomethyl)-2-methoxy-1- 262.2(trifluoromethyl)benzyl)oxy)azetidine; (trifluoromethyl)benzene [M + H]⁺trifluoroacetate salt BB56 3-((3-Fluoro-5- 3-Fluoro-5- 250.1(trifluoromethyl)benzyl)oxy)azetidine; (trifluoromethyl)benzyl 4- [M +H]⁺ trifluoroacetate salt methylbenzenesulfonate (BB87) BB603-((3-Chloro-4- 4-(Bromomethyl)-2-chloro-1- 266.1(trifluoromethyl)benzyl)oxy)azetidine; (trifluoromethyl)benzene [M + H]⁺trifluoroacetate salt BB62 3-((2-Fluoro-4- 1-(Bromomethyl)-2-fluoro-4-318.3 (trifluoromethyl)benzyl)oxy)-3- (trifluoromethyl)benzene and [M +H]⁺ (trifluoromethyl)azetidine; Tert-butyl 3-hydroxy-3- trifluoroacetatesalt (trifluoromethyl)azetidine-1- carboxylate (CAS: 398489-42-4) BB633-((2-Fluoro-4- 1-(Bromomethyl)-2-fluoro-4- 264.1(trifluoromethyl)benzyl)oxy)-3- (trifluoromethyl)benzene and [M + H]⁺methylazetidine; trifluoroacetate salt Tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (CAS: 1104083-23-9) BB643-((2,4-Difluoro-5- 1-(Bromomethyl)-2,4-difluoro-5- 268.1(trifluoromethyl)benzyl)oxy)azetidine; (trifluoromethyl)benzene [M + H]⁺trifluoroacetate salt BB65 3-((2-Fluoro-5- 2-(Bromomethyl)-1-fluoro-4-250.1 (trifluoromethyl)benzyl)oxy)azetidine (trifluoromethyl)benzene[M + H]⁺ trifluoroacetate salt BB66 3-((2-Fluoro-5-4-(Bromomethyl)-2-fluoro-1- 250.1 (trifluoromethyl)benzyl)oxy)azetidine;(trifluoromethyl)benzene [M + H]⁺ trifluoroacetate salt BB673-((2-Methoxy-4- 1-(Bromomethyl)-2-methoxy-4- 262.2(trifluoromethyl)benzyl)oxy)azetidine; (trifluoromethyl)benzene [M + H]⁺trifluoroacetate salt BB68 3-((4-Chloro-2- 1-(Bromomethyl)-4-chloro-2-266.2 (trifluoromethyl)benzyl)oxy)azetidine; (trifluoromethyl)benzene[M + H]⁺ trifluoroacetate salt BB88 3-[(2,4-1-(Bromomethyl)-2,4-dichloro- 232.1 dichlorophenyl)methoxy]azetidinebenzene [M + H]⁺ BB170 3-((3,4- 4-(Bromomethyl)-1,2-dichloro- 232.1Dichlorobenzyl)oxy)azetidine; benzene [M + H]+ 2,2,2-trifluoroacetateBB171 3-((2,5- 2-(Bromomethyl)-1,4-dichloro- 232.1Dichlorobenzyl)oxy)azetidine; benzene [M + H]+ 2,2,2-trifluoroacetateBB172 3-((3- 3-(Bromomethyl)- 248.1(Trifluoromethoxy)benzyl)oxy)azetidine; trifluoromethoxy-benzene [M +H]+ 2,2,2-trifluoroacetate BB173 2-Methyl-3-((4-methyl-3-tert-Butyl-3-hydroxy-2- 266.2 (trifluoromethyl)benzyl)oxy)azetidine;methylazetidine-1-carboxylate [M + H]+ 2,2,2-trifluoroacetate and4-(bromomethyl)-1-methyl-2- (trifluoromethyl)benzene BB1783-(((2-Fluoro-4- tert-Butyl 3- 264.2 (trifluoromethyl)benzyl)oxy)methyl)(hydroxymethyl)azetidine-1- [M + H]+ azetidine; 2,2,2-trifluoroacetatecarboxylate and 1-(Bromomethyl)-2-fluoro-4- (trifluoromethyl)benzeneBB180 [4-(Azetidin-3-yloxymethyl)-3- (4-(Bromomethyl)-3- 308.2fluoro-phenyl]-pentafluoro-□6- fluorophenyl)pentafluoro-□6- [M + H]+sulfane; 2,2,2-trifluoroacetate sulfane BB185 3-((2-Fluoro-4- tert-Butyl3-hydroxy-3- 332.2 (trifluoromethyl)benzyl)oxy)-3-(trifluoromethyl)pyrrolidine-1- [M + H]+ (trifluoromethyl)pyrrolidine;carboxylate and 2,2,2-trifluoroacetate 1-(Bromomethyl)-2-fluoro-4-(trifluoromethyl)benzene BB187 3-[[2,4- 1-(Bromomethyl)-2,4- 336.2bis(Trifluoromethyl)phenyl]methoxy]azetidine bis(trifluoromethyl)benzene[M + H]+ BB188 3-[[2-Methyl-3- 1-(Bromomethyl)-2-methyl-3- 246.1(trifluoromethyl)phenyl]methoxy]azetidine (trifluoromethyl)benzene [M +H]+ BB189 3-[[2-Methyl-4- 1-(Bromomethyl)-2-methyl-4- 262.1(trifluoromethoxy)phenyl]methoxy]azetidine (trifluoromethoxy)benzene[M + H]+ BB190 2-Methyl-3-[[2-methyl-4- 1-(Bromomethyl)-2-methyl-4-276.2 (trifluoromethoxy)phenyl]methoxy]azetidine(trifluoromethoxy)benzene [M + H]+ and tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate BB191 2-Methyl-3-[[2-methyl-3-1-(Bromomethyl)-2-methyl-3- 260.2(trifluoromethyl)phenyl]methoxy]azetidine (trifluoromethyl)benzene [M +H]+ and tert-Butyl 3-hydroxy-2- methylazetidine-1-carboxylate BB2073-[[4-Fluoro-2- 1-(Chloromethyl)-4-fluoro-2- 250.2(trifluoromethyl)phenyl]methoxy]azetidine; (trifluoromethyl)benzene [M +H]+ 4-methylbenzenesulfonate (CAS RN 248262-29-5) BB212 3-[[3-Fluoro-4-4-(Bromomethyl)-2-fluoro-1- Used(trifluoromethoxy)phenyl]methoxy]azetidine; (trifluoromethoxy )benzenewithout 2,2,2-trifluoroacetate purification BB217 3-((4-Methyl-3-4-(Bromomethyl)-1-methyl-2- 246.2 (trifluoromethyl)benzyl)oxy)azetidine;(trifluoromethyl)benzene. [M + H]+ 2,2,2-trifluoroacetate tBuOK as base

In analogy to BB129, intermediates BB12O, BB25 and BB6T of the followingtable were prepared from the commercially available phenols. Wheretrifluoroacetate salts are indicated, the crude product resulting fromconcentration of the reaction mixture was used directly without furtherneutralization or purification.

BB No. Systematic Name Starting material MS, in/z BB20 3-((2-Fluoro-4-2-Fluoro-4- 250.1 (trifluoromethyl)phenoxy)methyl)azetidine;(trifluoromethyl)phenol [M + H]⁺ trifluoroacetate salt (CAS RN:77227-78-2) BB25 3-[(2-Chloro-4- 2-Chloro-4-fluorophenol 216.1fluorophenoxy)methyl]azetidine (CAS RN: 1996-41-4) [M + H]⁺ (purified byRP-HPLC) BB61 3-((2-Chloro-4- 2-Chloro-4-fluorophenol 234.1fluorophenoxy)methyl)-3- (CAS RN: 1996-41-4) [M + H]⁺ fluoroazetidine;and trifluoroacetate salt tert-Butyl 3-fluoro-3-(hydroxymethyl)azetidine-1- carboxylate (CAS: 1126650-66-5)

In analogy to BB126, intermediates BB21- BB24 and BB28 of the followingtable were prepared from the commercially available phenols.

BB No. Systematic Name Starting material MS, m/z BB21 4-((4-Fluoro-2-4-Fluoro-2- 278.1 (trifluoromethyl)phenoxy)methyl)piperidine;(trifluoromethyl)phenol [M + H]⁺ hydrochloride salt (CAS: 130047-19-7)BB22 4-[[2-Fluoro-4- 2-Fluoro-4- 278.0(trifluoromethyl)phenoxy]methyl]piperidine; (trifluoromethyl)phenol [M +H]⁺ hydrochloride salt (CAS: 77227-78-2) BB23 4-((2-Chloro-4-2-Chloro-4- 294.1 (trifluoromethyl)phenoxy)methyl)piperidine;(trifluoromethyl)phenol [M + H]⁺ hydrochloride salt (CAS: 35852-58-5)BB24 5-Fluoro-2-(piperidin-4- 5-Fluoro-2-hydroxybenzonitrile 235.1ylmethoxy)benzonitrile; (CAS: 91407-41-9) [M + H]⁺ hydrochloride saltBB28 4-[(4-Fluoro-2-methyl- 4-Fluoro-2-methylphenol 224.0phenoxy)methyl]piperidine; (CAS: 452-72-2) [M + H]⁺ hydrochloride saltBB170 3-((3,4- 4-(Bromomethyl)-1,2- 232.1 Dichlorobenzyl)oxy)azetidinedichlorobenzene [M + H]+ 2,2,2-trifluoroacetate BB171 3-((2,5-2-(Bromomethyl)-1,4- 232.1 Dichlorobenzyl)oxy)azetidine dichlorobenzene[M + H]+ 2,2,2-trifluoroacetate BB172 3-((3- 3-(Bromomethyl)- 248.1(Trifluoromethoxy)benzyl)oxy)azetidine trifluoromethoxy-benzene [M + H]+2,2,2-trifluoroacetate BB173 2-Methyl-3-((4-methyl-3-tert-Butyl-3-hydroxyl- 266.2 (trifluoromethyl)benzyl)oxy)azetidinemethylazetidine-1-carboxylate [M + H]+ 2,2,2-trifluoroacetate and4-(Bromomethyl)-1-methyl-2- (trifluoromethyl)benzene BB1783-(((2-Fluoro-4- tert-Butyl 3- 264.2(trifluoromethyl)benzyl)oxy)methyl)azetidine (hydroxymethyl)azetidine-1-[M + H]+ 2,2,2-trifluoroacetate carboxylate and1-(Bromomethyl)-2-fluoro-4- (trifluoromethyl)benzene BB180[4-(Azetidin-3-yloxymethyl)-3- (4-Bromomethyl)-3- 308.2fluoro-phenyl]-pentafluoro-□6- fluorophenyl)pentafluoro-□6- [M + H]+sulfane 2,2,2-trifluoroacetic acid sulfane BB185 3-((2-Fluoro-4-tert-Butyl 3-hydroxy-3- 332.2 (trifluoromethyl)benzyl)oxy)-3-(trifluoromethyl)pyrrolidine-1- [M + H]+ (trifluoromethyl)pyrrolidine2,2,2- carboxylate trifluoroacetate and 1-(Bromomethyl)-2-fluoro-4-(trifluoromethyl)benzene BB187 3-[[2,4- 1-(Bromomethyl)-2,4- 336.2bis(Trifluoromethyl)phenyl]methoxy]azetidine bis(trifluoromethyl)benzene[M + H]+ BB188 3-[[2-Methyl-3- 1-(Bromomethyl)-2-methyl-3- 246.1(trifluoromethyl)phenyl]methoxy]azetidine (trifluoromethyl)benzene [M +H]+ BB189 3-[[2-Methyl-4- 1-(Bromomethyl)-2-methyl-4- 262.1(trifluoromethoxy)phenyl]methoxy]azetidine (trifluoromethoxy)benzene[M + H]+ BB190 2-Methyl-3-[[2-methyl-4- 1-(Bromomethyl)-2-methyl-4-276.2 (trifluoromethoxy)phenyl]methoxy]azetidine(trifluoromethoxy)benzene [M + H]+ and tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate BB191 2-Methyl-3-[[2-methyl-3-1-(Bromomethyl)-2-methyl-3- 260.2(trifluoromethyl)phenyl]methoxy]azetidine (trifluoromethyl)benzene [M +H]+ and tert-Butyl 3-hydroxy-2- methylazetidine-1-carboxylate BB2073-[[4-Fluoro-2- 1-(Chloromethyl)-4-fluoro-2- 250.2(trifluoromethyl)phenyl]methoxy]azetidine; (trifluoromethyl)benzene [M +H]+ 4-methylbenzenesulfonate (CAS RN 248262-29-5) BB212 3-[[3-Fluoro-4-4-(Bromomethyl)-2-fluoro-1- Used(trifluoromethoxy)phenyl]methoxy]azetidine; (trifluoromethoxy)benzenewithout 2,2,2-trifluoroacetate purification BB217 3-((4-Methyl-3-4-(Bromomethyl)-1-methyl-2- 246.2 (trifluoromethyl)benzyl)oxy)azetidine;(trifluoromethyl)benzene. [M + H]+ 2,2,2-trifluoroacetate tBuOK as baseBB218 3-((2-Fluoro-6- tert-Butyl 3-mercaptoazetidine- 266.2(trifluoromethyl)benzyl)thio)azetidine 1-carboxylate and [M + H]+2,2,2-trifluoroacetate 2-(Bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene

Method D1 BB9 4-[2-Chloro-4-(trifluoromethyl)phenoxy]piperidine;Trifluoroacetate Salt

A mixture of tert-butyl4-[2-chloro-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (750.0mg, 1.97 mmol) in DCM (20 mL) and TFA (0.76 mL) was stirred at 20° C.for 12 h. The mixture was concentrated. The residue was dissolved in H₂O(20 mL) and washed twice with PE:EA=10:1 (20 mL each). The aqueous layerwas lyophilized to give the desired product as light yellow solid (716mg, 1.82 mmol, 87.8%). MS (ESI): m/z=280.1 [M+H]⁺.

Step a) tert-Butyl4-[2-chloro-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

A mixture of 2-chloro-4-(trifluoromethyl)phenol (500 mg, 2.54 mmol),1-Boc-4-hydroxypiperidine (768 mg, 3.82 mmol) and triphenylphosphine(1334 mg, 5.09 mmol) in THF (10 mL) was stirred at 0° C. untilcompletely dissolved. DIAD (1542 mg, 7.63 mmol) was slowly addeddropwise at 0° C. The mixture was stirred at 20° C. for 3 h and thenconcentrated under vacuum. The residue was purified by prep-HPLC to givethe desired compound as light yellow solid (760 mg, 2 mmol, 78.7%yield). MS (ESI): m/z=324.0 [M−56+H]⁺.

BB57 3-(((2-Fluoro-6-(trifluoromethyl)benzyl)oxy)methyl)azetidine;Trifluoroacetate Salt

To a solution of tert-butyl3-(((2-fluoro-6-(trifluoromethyl)benzyl)oxy)methyl)azetidine-1-carboxylate(158 mg, 435 μmol) in DCM (1.74 mL) was added TFA (793 mg, 536 μL, 6.96mmol) and the reaction was stirred at room temperature for 3 h. Thereaction mixture was concentrated to give3-(((2-fluoro-6-(trifluoromethyl)benzyl)oxy)methyl)azetidine;trifluoroacetate salt (202 mg, 434 μmol, 99.7% yield) as a colorlessoil. The crude was used without further purification. MS (ESI):m/z=264.1 [M+H]⁺.

Step a) Tert-butyl3-(((2-fluoro-4-(trifluoromethyl)benzyl)oxy)methyl)azetidine-1-carboxylate

To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate(100 mg, 534 μmol) in dry THF (2.67 mL) was added potassiumtert-butoxide 1.65 M solution in THF (340 μL, 561 μmol) and the turbidreaction mixture was stirred at RT for 15 min followed by addition of1-(bromomethyl)-2-fluoro-6-(trifluoromethyl)benzene (137 mg, 534 μmol).The reaction mixture was then stirred at room temperature for 3 h. Thecrude reaction was diluted with ethyl acetate and extracted with sat.aq. NaHCO₃ solution, the organic phase was collected and the aqueousphase was back-extracted with ethyl acetate. The combined organic phaseswere dried over sodium sulfate and evaporated down to dryness to yield aclear oil. The crude was immobilized on Isolute and purified by columnchromatography eluting with 0 to 30% EtOAc in heptanes to affordtert-butyl3-(((2-fluoro-6-(trifluoromethyl)benzyl)oxy)methyl)azetidine-1-carboxylate(158 mg, 413 μmol, 77.3% yield) as a colorless oil. MS (ESI): m/z=308.1[M−56+H]⁺

Method D2 BB104-[[2-Cyclopentyl-4-(trifluoromethyl)phenyl]methyl]piperidine; FormicAcid Salt

A mixture of tert-butyl4-[[2-cyclopentyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate(440 mg, 0.610 mmol) and 5.0 mL of 4 M HCl in EtOAc in EtOAc (10 mL) wasstirred at 20° C. for 12 h. The mixture was concentrated under vacuum.The residue was re-dissolved in H₂O (5 mL), washed twice with PE:EA(3:1; 10 mL each) and the layers were separated. The aqueous layer waspurified by prep-HPLC to give the desired compound as light yellow solid(124 mg, 0.350 mmol, 65.3% yield). MS (ESI): m/z=312.2 [M+H]⁺.

Step a) tert-Butyl4-[[2-cyclopentyl-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate

A solution of tert-butyl4-[[2-bromo-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate(500 mg, 1.19 mmol), cyclopentyl bromide (266 mg, 1.78 mmol),Ir(dF(CF₃)ppy)₂(dtbbpy)PF₆ (13.4 mg, 0.010 mmol, CAS RN 870987-63-6),NiCl₂.glyme (0.77 mg, 0.060 mmol), dtbbpy (19.2 mg, 0.070 mmol, CAS RN72914-19-3), TTMSS (296 mg, 1.19 mmol, CAS RN 1873-77-4) and Na₂CO₃ (252mg, 2.38 mmol) in DMF (20 mL) was degassed by bubbling argon stream for20 min. The reaction mixture was irradiated with Blue LED (4×1) at 25°C. for 16 h. The mixture was diluted with H₂O and then extracted threetimes with EtOAc (100 mL each). The combined organic layer was washedwith brine, dried over sodium sulfate, filtered and concentrated. Theresidue was purified by prep-HPLC to give the compound as a colorlessoil (460 mg, 1.12 mmol, 53.8%). MS (ESI): m/z=354.1 [M−56+H]⁺.

Step b) tert-Butyl 4-[[2-cyclopentyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate

To a mixture of tert-butyl4-[[2-cyclopentyl-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate(460 mg, 0.640 mmol) in EtOAc (10 mL) was added wet Pd/C (40 mg), andthen the mixture was stirred at 20° C. for 12 h under H₂ (1520 mmHg).The mixture was filtered and the filtrate was concentrated to give thecompound as colorless oil (460 mg, 1.12 mmol, 99.5%). MS (ESI):m/z=356.1 [M+H−56]⁺.

B111 2-(4-Piperidylmethyl)-1,3-benzoxazole; Formic Acid Salt

A solution of 2-aminophenol (1.0 g, 9.16 mmol) and1-Boc-4-piperidylacetic acid (2.68 g, 11 mmol) in polyphosphoric acid(2.2 g) was stirred at 180° C. for 2 h. The mixture was diluted with amixture of 12M aqueous NH₄OH solution and ice to reach pH>7, and thenextracted three times with EtOAc (10 mL each). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated, and the residue was purified by prep-HPLC to give thedesired compound as a brown oil (251 mg, 0.960 mmol, 9.7%). MS (ESI):m/z=217.2 [M+H]⁺.

Method D3 BB13 4-[4-Chloro-3-(4-chlorophenyl)phenoxy]piperidine;Hydrochloride Salt

A solution of tert-butyl4-[4-chloro-3-(4-chlorophenyl)phenoxy]piperidine-1-carboxylate (1000 mg,2.37 mmol) in a 4 M solution of HCl in dioxane (50 mL) was stirred at20° C. for 12 h. The mixture was concentrated to give the title compoundas a white solid (845 mg, 2.35 mmol, 96.2%). MS (ESI): m/z=322.0 [M+H]⁺.

Step a) tert-Butyl 4-(3-bromo-4-chloro-phenoxy) piperidine-1-carboxylate

A mixture of 3-bromo-4-chlorophenol (1000 mg, 4.82 mmol),1-Boc-4-hydroxypiperidine (1164 mg, 5.78 mmol) and triphenylphosphine(2529 mg, 9.64 mmol) was stirred in THF (10 mL) until completelydissolved. Then DIAD (1948 mg, 9.64 mmol) was slowly added drop wise at0° C. The mixture was stirred at 20° C. for 12 h, concentrated and theresidue was purified by reversed flash chromatography to give thecompound as yellow oil (1300 mg, 3.33 mmol, 69.0%). MS (ESI): m/z=336.0[M−56+H]⁺.

Step b) tert-Butyl4-[4-chloro-3-(4-chlorophenyl)phenoxy]piperidine-1-carboxylate

To a solution of tert-butyl4-(3-bromo-4-chloro-phenoxy)piperidine-1-carboxylate (1150 mg, 2.94mmol) and 4-chlorophenylboronic acid (506 mg, 3.24 mmol), Na₂CO₃ (1248mg, 11.8 mmol) in 1,4-dioxane (20 mL) and H₂O (5 mL) was addedtetrakis(triphenylphosphine)palladium(0) (340 mg, 0.290 mmol, CAS RN14221-01-3), and the mixture was stirred at 110° C. under N₂ atmospherefor 12 h. The mixture was filtered, the filtrate was concentrated, andthe residue was purified by silica gel column chromatography, elutingwith a 5-20% EtOAc—PE gradient to give the desired compound as lightyellow oil (1100 mg, 2.6 mmol, 88.5%). MS (ESI): m/z=366.1 [M−56+H]⁺.

BB144-[[2-(1H-Pyrazol-4-yl)-4-(trifluoromethyl)phenyl]methyl]piperidine;Trifluoroacetate Salt

To a mixture of tert-butyl4-[[2-(1-tert-butoxycarbonylpyrazol-4-yl)-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate (150.0 mg, 0.290 mmol) in DCM (5mL) was added TFA (1.0 mL). The mixture was stirred at 20° C. for 15 h.The mixture was concentrated under vacuum and then lyophilized to givethe title compound as light yellow gum (149 mg, 0.280 mmol, 85.1%yield). MS (ESI): m/z=310.0 [M+H]⁺.

Step a) tert-Butyl4-[[2-(I-tert-butoxycarbonylpyrazol-4-yl)-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate

A mixture of tert-butyl4-[[2-bromo-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate(600 mg, 1.43 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyrazole-1-carboxylate (846 mg,2.86 mmol) and K₂CO₃ (592 mg, 4.28 mmol) in DMF (10 mL) and H₂O (0.5 mL)was stirred at 80° C. for 12 h. The mixture was poured into H₂O (30 mL)and extracted twice with EtOAc (50 mL each). The combined organic layerswere washed with brine (30 mL), dried over Na₂SO₄ and filtered. Thefiltrated was concentrated in vacuum to give the compound as lightyellow oil (520 mg, 1.02 mmol, 71.8% yield). MS (ESI): m/z=308.1 [M+H]⁺.

Step b) tert-Butyl4-[[2-(1-tert-butoxycarbonylpyrazol-4-yl)-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate

A mixture of tert-butyl4-[[2-(1-tert-butoxycarbonylpyrazol-4-yl)-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate(180 mg, 0.350 mmol) and wet Pd/C (18 mg) in EtOAc (10 mL) was stirredat 30° C. for 24 h under H₂ atmosphere (˜1520 mm Hg). The mixture wasfiltered and concentrated under vacuum to give the compound as brown oil(150 mg, 0.290 mmol, 83%). MS (ESI): m/z=354.1 [M-56-100+H]⁺.

BB18 4-[2-(2-Chlorophenyl)ethynyl]piperidine

To a suspension of tert-butyl4-((2-chlorophenyl)ethynyl)piperidine-1-carboxylate (0.05 g, 0.156 mmol)in MeOH (3 mL) was added 4 M HCl in dioxane (0.391 mL, 1.56 mmol) andthe reaction mixture was stirred at room temperature for 2 h. Themixture was evaporated to dryness and the residue triturated indiisopropyl ether, filtered off and further dried under high vacuum togive the title compound as a white solid as the hydrochloride salt (0.02g, 50%). MS (ESI): m/z=220.1 [M+H]⁺.

Step a) tert-Butyl 4-[2-(2-chlorophenyl)ethynyl]piperidine-1-carboxylate

In a sealed tube, a mixture of tert-butyl4-ethynylpiperidine-1-carboxylate (0.1 g, 0.478 mmol, CAS RN287192-97-6,), 1-bromo-2-chlorobenzene (0.084 mL, 0.717 mmol), copper(I) iodide (0.002 g, 0.009 mmol), TEA (0.666 mL, 4.78 mmol) andbis(triphenylphosphine)palladium(II) chloride (0.027 g, 0.038) in THF(2.8 mL) was degassed for 5 min under Argon. The reaction mixture wasthen heated to 70° C. and stirred for 4 h. The mixture was filtered offover a pad of Dicalite, washed with EtOAc and the mother liquors wereevaporated to dryness. The residue was purified by silica gel flashchromatography, eluting with a gradient of 0-50% EtOAc/n-heptane to givethe title compound as a white solid (0.05 g, 33%). MS (ESI): m/z=264.1[M-56+H]⁺.

BB48a tert-Butyl4-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate

A degassed solution of tert-butyl 4-methylenepiperidine-1-carboxylate(4465 mg, 22.6 mmol, CAS RN 159635-49-1) in 9-BBN (45.3 mL, 22.6 mmol)was refluxed for 1 h. After cooling to room temperature, the solutionwas added into a solution of 4-bromo-3-fluorobenzotrifluoride (5.0 g,20.6 mmol, CAS RN 40161-54-4), Pd(dppf)Cl₂ (1514 mg, 2.06 mmol) andK₂CO₃ (5687 mg, 41.1 mmol) in DMF (50 mL) and water (5 mL). Theresulting mixture was heated at 80° C. for 5 h. After the mixture wascooled to room temperature and poured into water, the pH was adjusted to11 with 10% aqueous NaOH solution, and the mixture was extracted withEtOAc. The combined organic extracts were dried with brine and Na₂SO₄,filtered, and evaporated to give a residue, which was further purifiedby column chromatography (silica gel, PE:EtOAc=10:1 to 5:1) to give thecompound as light yellow solid (240 mg, 3.2%). MS (ESI): m/z=306[M+H−56]⁺.

BB51a

A mixture of tert-butyl4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate(1000 mg, 2.62 mmol) and PtO₂ (100 mg, 0.440 mmol) in EtOAc (20 mL) wasstirred at 20° C. for 12 h under H₂ atmosphere (1520 mmHg). The mixturewas filtered and the filtrate concentrated to furnish the compound aslight yellow solid (940 mg, 93.5%). MS (ESI): m/z=328.2 [M+H]⁺.

Step a) 2-Bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene

A mixture of 2-bromo-1-methyl-4-(trifluoromethyl)benzene (5.5 g, 23.0mmol, CAS RN 128-08-5), benzoyl peroxide (835 mg, 3.45 mmol) and NBS(4.07 g, 23.01 mmol) in CCl₄ (50.0 mL, 23.0 mmol) was stirred at 70° C.for 5 h. The mixture was poured into water (20 mL) and extracted twicewith DCM (20 mL each). The combined organic layer was washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated in vacuum to givethe desired compound as light yellow oil which was used in the next stepwithout further purification (7.1 g, 97%).

Step b) 2-Bromo-1-(diethoxyphosphorylmethyl)-4-(trifluoromethyl)benzene

A mixture of 2-bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene (7.1 g,22.3 mmol) and triethyl phosphite (30 mL) was stirred at 155° C. for 5h. The mixture was concentrated in vacuum to remove triethyl phosphite,the residue was diluted with water (100 mL) and extracted three timeswith EtOAc (100 mL each). The combined organic layers were washed withbrine (100 mL), dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by column chromatography(PE:EtOAc=100:1 to 10:1) to give the compound as light yellow oil whichwas used without further purification in the next step (8 g, 95.5%).

Step c) tert-Butyl4-(2-bromo-4-(trifluoromethyl)benzylidene)piperidine-1-carboxylate

To a mixture of2-bromo-1-(diethoxyphosphorylmethyl)-4-(trifluoromethyl)benzene (6.9 g,18.4 mmol) in THF (100 mL) was added sodium hydride (2.21 g, 55.2 mmol)at 0° C. The mixture was stirred at 0° C. for 1 h, then1-Boc-4-piperidone (7.33 g, 36.79 mmol, CAS RN 79099-07-3) was added andthe mixture was stirred at 20° C. for 12 h. The mixture was poured intowater (100 mL) and extracted three times with EtOAc (100 mL each). Thecombined organic layers were washed with brine (100 mL), dried overNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bycolumn chromatography (PE:EA=100:1 to 50:1) to yield the desiredcompound as off-white solid (4 g, 51.7%). MS (ESI): m/z=365.9 [M−56+H]⁺.

Step d) tert-butyl4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate

A mixture of tert-butyl4-[[2-bromo-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate(2.0 g, 4.76 mmol), cyclopropylboronic acid (818 mg, 9.52 mmol, CAS RN411235-57-9) and potassium carbonate (1973 mg, 14.3 mmol) in DMF (10 mL)and water (0.5 mL) was stirred at 80° C. under nitrogen atmosphere for12 h. The mixture was poured into water (50 mL), extracted three timeswith EtOAc (50 mL each). The combined organic layers were washed withbrine (50 mL), dried over Na₂SO₄ and concentrated in vacuum. The residuewas purified by prep-HPLC to give the compound as light yellow oil (1020mg, 56.2% yield). MS (ESI): m/z=326.0 [M−56+H]⁺.

BB53a tert-Butyl 3-[(4-chlorophenyl)methoxy]pyrrolidine-1-carboxylate

A solution of N-Boc-3-hydroxypyrrolidine (1.0 g, 5.34 mmol) and4-chlorobenzyl bromide (1.32 g, 6.41 mmol) in ACN (10 mL) was addedpotassium carbonate (1.48 g, 10.68 mmol). The mixture was stirred at 80°C. for 15 h. Then the mixture was concentrated and diluted with waterand extracted three times with EtOAc (10 mL each). The combined organiclayers were concentrated to give the desired compound as colorless oil(326 mg, 19.6% yield) MS (ESI): m/z=256.0 [M−56+H]⁺.

Method D4 BB70 3-[4-(Trifluoromethyl)phenoxy]azetidine

To a solution of tert-butyl3-[4-(trifluoromethyl)phenoxy]azetidine-1-carboxylate (500 mg, 1.58mmol, BB70a) in DCM (3 mL) was added TFA (1.0 mL, 0.950 mmol) at 25° C.,the reaction was stirred at this temperature for 12 h. The mixture wasconcentrated and the residue was purified via prep-HPLC to provide thecompound as colorless solid (150 mg, 0.690 mmol, 43.8%). MS (ESI):m/z=218.1 [M+H]⁺.

BB72a tert-Butyl4-(4-chloro-3-cyclopropyl-phenoxy)piperidine-1-carboxylate

To a solution of tert-butyl4-(3-bromo-4-chloro-phenoxy)piperidine-1-carboxylate (500 mg, 1.28 mmol,BB90), potassium carbonate (354 mg, 2.56 mmol) and cyclopropylboronicacid (121 mg, 1.41 mmol) in 1,4-dioxane (5 mL) and water (1 mL) wasadded [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II)(187.28 mg, 0.260 mmol). The mixture was stirred at 100° C. undernitrogen atmosphere for 12 h. The reaction mixture was filtered and thefiltrate was diluted with EtOAc (30 mL), washed with water and thenbrine, the organic phase was dried over Na₂SO₄, concentrated. Theresidue was purified by silica gel column (eluting with a gradient of5%-10% EtOAc-PE) to give the compound as light yellow oil (220 mg,48.9%). MS (ESI): m/z=296.1 [M−56+H]⁺.

BB73a tert-Butyl 4-(4-chloro-3-morpholino-phenoxy)piperidine-1-carboxylate

To a solution of tert-butyl4-(3-bromo-4-chloro-phenoxy)piperidine-1-carboxylate (500 mg, 1.28 mmol,BB90), cesium carbonate (834 mg, 2.56 mmol),(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (159 mg, 0.260mmol) and morpholine (112 mg, 1.28 mmol) in DMF (10 mL) was addedtris(dibenzylideneacetone)dipalladium(0) (187 mg, 0.260 mmol) and themixture was stirred at 110° C. under nitrogen atmosphere for 12 h. Thereaction mixture was filtered, the filtrate was diluted with EtOAc (30mL), washed with water and then brine, the organic phase was dried overNa₂SO₄, and concentrated. The residue was purified by silica gel column(eluting with a gradient of 5%-10% EtOAc-PE) to give the desiredcompound (360 mg, 70.9% yield) as light yellow oil. MS (ESI): m/z=397.1[M+H]⁺.

BB74a tert-Butyl4-[2-methyl-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

To a solution of tert-butyl4-[2-bromo-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (2.0 g,4.71 mmol, BB74b) in THF (40 mL) was added lithium methide (11.8 mL,18.9 mmol) dropwise at −70° C. The mixture was stirred at −70° C. for 1h and then stirred at 20° C. for 12 h.

The mixture was poured into ice water (100 mL) and extracted three timeswith EtOAc (50 mL each). The combined organic layer was washed withbrine (100 mL), dried over Na₂SO₄ and filtered. The filtrate wasconcentrated under vacuum to yield the compound as light yellow solid(780 mg, 46%). MS (ESI): m/z=260.1 [M-100+H]⁺.

BB75a tert-Butyl4-[2-cyano-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

To a solution of zinc cyanide (2214 mg, 18.9 mmol) and tert-butyl4-[2-bromo-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (1600 mg,3.77 mmol, BB74b) in DMA (30 mL) was added dppf (627 mg, 1.13 mmol),N,N-diisopropylethylamine (1.97 mL, 11.3 mmol), Zinc dust (245 mg, 3.77mmol) and Pd₂(dba)₃ (1036 mg, 1.13 mmol) at 20° C., then the mixture wasstirred at 140° C. under nitrogen atmosphere for 4 h. The mixture wasfiltered. The filtrate was poured into water (100 mL) and extractedthree times with EtOAc (50 mL each). The combined organic layer waswashed with brine (50 mL), dried over Na₂SO₄ and filtered. The filtratewas concentrated over vacuum to give the title compound as light brownsolid (2.3 g, crude). MS (ESI): m/z=315.0 [M−56+H]⁺.

BB76a tert-Butyl4-(oxazolo[5,4-c]pyridin-2-ylmethyl)piperidine-1-carboxylate

To a solution of hexachloroethane (2.47 g, 10.4 mmol) in toluene (20 mL)was added triphenylphosphine (3.28 g, 12.5 mmol) and NEt₃ (4.65 mL, 33.4mmol). The mixture was stirred at 80° C. for 5 min, then tert-butyl4-[2-[(3-hydroxy-4-pyridyl)amino]-2-oxo-ethyl]piperidine-1-carboxylate(1.4 g, 4.17 mmol) was added and stirred at 80° C. for 12 h. The mixturewas concentrated to remove toluene, then diluted with water (100 mL) andextracted three times with EtOAc (50 mL each). The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated. The crude was purified by silica gel chromatography(PE:EtOAc=10:1 to 1:0) to give the compound as a yellow oil (814 mg, 21%yield). MS (ESI): m/z=318.1 [M+H]⁺.

Step a) tert-Butyl4-[2-[(3-hydroxy-4-pyridyl)amino]-2-oxo-ethyl]piperidine-1-carboxylate

A solution of 4-aminopyridin-3-ol (3.0 g, 27.3 mmol) and1-Boc-4-piperidylacetic acid (7.95 g, 32.7 mmol) in DMF (30 mL) wasadded HOBt (6.26 g, 40.9 mmol), EDCI (6.34 g, 40.87 mmol) and NEt₃(11.39 mL, 81.74 mmol). The mixture was stirred at 20° C. for 15 h. Thenthe mixture was concentrated, the residue taken up in water (100 mL),and then extracted three times with EtOAc (20 mL each). The organicphase was washed with brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by reversed phase chromatography and lyophilized togive two batches of the desired compound. Batch 1 as colorless solid(1.2 g, 85% purity, 11.1%), and batch 2 as colorless solid (520 mg,76.7% purity, 4.4% yield). MS (ESI): m/z=336.1[M+H]⁺ for both batches.

BB77 4-Chloro-3-(2-piperidin-4-ylethynyl)pyridine

Intermediate BB77 was prepared in analogy to BB18, but using3-bromo-4-chloro-pyridine in step a), to give the title compound as anorange solid. MS (ESI): m/z=221.1 [M+H]⁺.

BB78 3-Chloro-2-(2-piperidin-4-ylethynyl)pyridine

Intermediate BB78 was prepared in analogy to BB18, but using2-bromo-3-chloro-pyridine in step a), to give the title compound as ayellow solid. MS (ESI): m/z=221.1 [M+H]⁺.

BB79 4-[2-(2-Chloro-4-fluorophenyl)ethynyl]piperidine

Intermediate BB79 was prepared in analogy to BB18, but using1-bromo-2-chloro-4-fluoro-benzene in step a), to give the title compoundas a white solid. MS (ESI): m/z=238.1 [M+H]⁺.

BB80 4-[2-(3-Chlorophenyl)ethynyl]piperidine

Intermediate BB80 was prepared in analogy to BB18, but using1-bromo-3-chlorobenzene in step a), to give the title compound as acolorless amorphous solid. MS (ESI): m/z=220.2 [M+H]⁺.

BB81 4-[2-(4-Chlorophenyl)ethynyl]piperidine

Intermediate BB81 was prepared in analogy to BB18, but using1-bromo-4-chlorobenzene in step a), to give the title compound as ayellow amorphous solid. MS (ESI): m/z=220.2 [M+H]⁺.

BB82 4-[2-(2-Chloro-4-chlorophenyl)ethynyl]piperidine

Intermediate BB82 was prepared in analogy to BB18, but using1-bromo-2,4-dichloro-benzene in step a), to give the title compound as alight yellow amorphous solid. MS (ESI): m/z=254.1[M+H]⁺.

BB83 4-[2-(2-Chlorophenyl)ethynyl]piperidin-4-ol

Intermediate BB83 was prepared in analogy to BB18, but using tert-butyl4-ethynyl-4-hydroxypiperidine-1-carboxylate (CAS RN 275387-83-2) in stepa), to give the title compound as a yellow amorphous solid. MS (ESI):m/z=218.1[M−H₂O+H]⁺.

BB84 3-[2-(2-Chlorophenyl)ethynyl]azetidine

To a solution tert-butyl3-[2-(2-chlorophenyl)ethynyl]azetidine-1-carboxylate (0.035 g, 0.120mmol) in DCM (0.6 mL) was added TFA (0.92.4 mL, 1.2 mmol) and thereaction mixture was stirred at room temperature for 2 h. The mixturewas diluted with DCM, poured into a saturated aq. NaHCO₃ solution andextracted with DCM. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered, evaporated and further dried on the highvacuum to give the crude title compound (0.02 g, 87%) as a light yellowoil. MS (ESI): m/z=192.0 [M+H]⁺.

Step a) tert-Butyl 3-[2-(2-chlorophenyl)ethynyl]azetidine-1-carboxylate

The compound was prepared in analogy to intermediate BB18, but usingtert-butyl 3-ethynylazetidine-1-carboxylate (CAS RN 287193-01-5) in stepa), to give the title compound as a white solid. MS (ESI): m/z=236.1[M−56+H]⁺.

BB85 3-[2-(2,4-Dichlorophenyl)ethynyl]azetidine

Intermediate BB85 was prepared in analogy to intermediate BB84, butusing 1-bromo-2,4-dichloro-benzene in step a), to give the titlecompound as a light yellow oil. MS (ESI): m/z=226.1 [M+H]⁺.

BB86 3-[2-(2-Chloro-4-fluoro-phenyl)ethynyl]azetidine

Intermediate BB86 was prepared in analogy to intermediate BB84, butusing 1-bromo-2-chloro-4-fluoro-benzene in step a), to give the titlecompound as a yellow oil. MS (ESI): m/z=210.1 [M+H]⁺.

In analogy to BB9a the following building blocks were prepared from therespective building blocks

BB No. Systematic Name Starting materials MS, m/z BB54a tert-Butyl4-[[2-methyl-4- tert-Butyl 4- 302.1 (trifluoromethyl)phenyl]methyl]methylenepiperidine-1- [M + H-56]⁺ piperidine-1-carboxylate carboxylate4-Bromo-3-methyl benzotrifluoride BB55a tert-Butyl 4-[[2-chloro-4-tert-Butyl 4- 322.0 (trifluoromethyl)phenyl]meth- methylenepiperidine-1-[M + H-56]⁺ yl]piperidine-1-carboxylate carboxylate 4-Bromo-3-chlorobenzotrifluoride

In analogy to BB15a the following building blocks were prepared from therespective building blocks.

BB No. Systematic Name Starting materials MS, m/z BB49a tert-Butyl3-[(2- 2-Chlorobenzyl bromide 256.0 chlorophenyl)methoxy]pyrrolidine-1-N-Boc-3-hydroxypyrrolidine [M-56 + H]⁺ carboxylate BB50a tert-Butyl3-[(3- 3-Chlorobenzyl bromide 256.0 chlorophenyl)methoxy]pyrrolidine-1-N-BOC-3-hydroxypyrrolidine [M-56 + H]⁺ carboxylate

In analogy to BB9 step a, the following building blocks were preparedfrom the respective starting materials.

BB No. Systematic Name Starting materials MS, m/z BB47a tert-Butyl3-[(2- 2-Chlorophenol 256.0 chlorophenoxy)methyl]pyrrolidine-1-tert-Butyl 3- [M-56 + H]⁺ carboxylate (hydroxymethyl)pyrrolidine-1-carboxylate BB52a tert-Butyl 3-[(4- 4-Chlorophenol 256.0chlorophenoxy)methyl]pyrrolidine-1- tert-Butyl 3- [M-56 + H]⁺carboxylate (hydroxymethyl)pyrrolidine-1- carboxylate BB70a tert-Butyl3-[4- 4-(Trifluoromethyl)phenol Used(trifluoromethyl)phenoxy]azetidine-1- tert-Butyl 3-hydroxyazetidine-1-without carboxylate carboxylate further purification BB71a tert-Butyl4-[4-chloro-3- 1-Boc-4-hydroxypiperidine 324.0(trifluoromethyl)phenoxy]piperidine-1- 4-Chloro-3- [M-56 + H]⁺carboxylate (trifluoromethyl)phenol BB74b tert-Butyl 4-[2-bromo-4-2-Bromo-4- 369.9 (trifluoromethyl)phenoxy]piperidine-1-(trifluoromethyl)phenol [M-56 + H]⁺ carboxylate1-BOC-4-hydroxypiperidine BB89a tert-Butyl 3-[(3- 3-Chlorophenol 256.0chlorophenoxy)methyl]pyrrolidine-1- tert-Butyl 3- [M-56 + H]⁺carboxylate (hydroxy methyl)pyrrolidine-1- carboxylate BB90 tert-Butyl4-(3-bromo-4-chloro- 3-Bromo-4-chlorophenol 336.0 phenoxy)piperidine-1-carboxylate 1-BOC-4-hydroxypiperidine [M-56 + H]⁺

Method D5 BB514-[[2-Cyclopropyl-4-(trifluoromethyl)phenyl]methyl]piperidine FormicAcid Salt

To a mixture of tert-butyl4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate(940 mg, 2.45 mmol, BB51a) in DCM (10 mL) was added TFA (2.0 mL, 2.45mmol). The mixture was stirred at 20° C. for 12 h. The mixture wasconcentrated under vacuum. The residue was purified twice by prep-HPLCto furnish the desired compound as light yellow gum (111 mg, 12.4%₀). MS(ESI): m/z=284.2 [M+H]⁺.

Step a) 2-Bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene

A mixture of 2-bromo-1-methyl-4-(trifluoromethyl)benzene (5.5 g, 23.0mmol, CAS RN 128-08-5), benzoyl peroxide (835 mg, 3.45 mmol) and NBS(4.07 g, 23.0 mmol) in CCl₄ (50.0 mL, 23.0 mmol) was stirred at 70° C.for 5 h. The mixture was poured into water (20 mL) and extracted twicewith DCM (20 mL each). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated in vacuum togive the compound as light yellow oil (7.1 g, 97%) which was used in thenext step without further purification.

Step b) 2-Bromo-1-(diethoxyphosphorylmethyl)-4-(trifluoromethyl)benzene

A mixture of 2-bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene (7.1 g,22.3 mmol,) and triethyl phosphite (30.0 mL) was stirred at 155° C. for5 h. The mixture was concentrated in vacuum to remove triethylphosphite. The residue was diluted with water (100 mL) and extractedthree times with EtOAc (100 mL each). The combined organic layers werewashed with brine (100 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography(PE:EA=100:1 to 10:1) to give the title compound as light yellow oil (8g, 21.3 mmol, 95.5%) which was used in the subsequent step withoutfurther purification.

Step c) tert-Butyl4-(2-bromo-4-(trifluoromethyl)benzylidene)piperidine-1-carboxylate

A mixture of2-bromo-1-(diethoxyphosphorylmethyl)-4-(trifluoromethyl)benzene (6.9 g,18.4 mmol) in THF (100 mL) was added NaH (2.21 g, 55.2 mmol) at 0° C.The mixture was stirred at 0° C. for 1 h, then 1-Boc-4-piperidone (7.33g, 36.8 mmol, CAS RN 79099-07-3) was added and the mixture was stirredat 20° C. for 12 h. The mixture was poured into water (100 mL) andextracted three times with EtOAc (100 mL each). The combined organiclayer was washed with brine (100 mL), dried over Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by columnchromatography (PE:EA=100:1 to 50:1) to yield the desired compound asoff-white solid (4 g, 9.52 mmol, 51.7%). MS (ESI): m/z=365.9 [M−56+H]⁺.

Step d) tert-Butyl 4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate

A mixture of tert-butyl4-[[2-bromo-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate(2.0 g, 4.76 mmol), cyclopropylboronic acid (818 mg, 9.52 mmol, CAS RN411235-57-9) and potassium carbonate (1973 mg, 14.3 mmol) in DMF (10 mL)and water (0.5 mL) was stirred at 80° C. for 12 h under nitrogenatmosphere. The mixture was poured into water (50 mL) and extractedthree times with EtOAc (50 mL each). The combined organic layers werewashed with brine (50 mL), dried over Na₂SO₄ and concentrated in vacuum.The residue was purified by prep-HPLC to give the compound as lightyellow oil (1020 mg, 56.2% yield) MS (ESI): m/z=326.0 [M−56+H]⁺.

Step e) tert-Butyl4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate

A mixture of tert-butyl4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate(1000 mg, 2.62 mmol) and PtO₂ (100 mg, 0.440 mmol) in EtOAc (20 mL) wasstirred at 20° C. for 12 h under hydrogen atmosphere (1520 mm Hg). Thenthe mixture was filtered and the filtrate was concentrated to yield thecompound as light yellow solid (940 mg, 93.5% yield). MS (ESI):m/z=328.2 [M+H]⁺.

Method D6 BB92 N-methyl-N-[4-(trifluoromethyl)phenyl]piperidin-4-amine;Trifluoroacetate Salt

To a solution of tert-butyl4-[N-methyl-4-(trifluoromethyl)anilino]piperidine-1-carboxylate (150 mg,0.420 mmol) in DCM (1 mL) was added TFA (0.1 mL) at 0° C. The mixturewas stirred at 25° C. for 12 h. The reaction mixture was concentrated invacuum. The residue was purified by pre-HPLC (in the presence of TFA) togive the desired product as yellow solid (120 mg, 77.0%). MS (ESI):m/z=259.2 [M+H]⁺.

Step a) tert-Butyl4-[4-(trifluoromethyl)anilino]piperidine-1-carboxylate

To a solution of p-trifluoromethylaniline (1.17 mL, 9.31 mmol, CAS RN455-14-1) in DCM (30 mL) was added AcOH (0.560 g, 9.31 mmol) and1-BOC-4-piperidone (2.78 g, 14.0 mmol, CAS RN 79099-07-3). Then 1MBH₃/THF solution (27.9 mL, 27.9 mmol) was added carefully at 0° C. undernitrogen atmosphere. The reaction mixture was stirred at 25° C. for 12h. The mixture was poured into saturated aqueous NH₄Cl solution (30 mL)and extracted three times with EtOAc. The combined organic layers werewashed twice with water H₂O, and then brine, dried over Na₂SO₄ andconcentrated in vacuum to afford yellow residue, which was purified bysilica gel column eluting with a gradient of PE:EtOAc (20:1 to 5:1) togive the desired product as white solid (2.0 g, 62.4%). MS (ESI):m/z=289.1 [M−56+H]⁺.

Step b) tert-Butyl4-[N-methyl-4-(trifluoromethyl)anilino]piperidine-1-carboxylate

To a solution of NaH (52.3 mg, 60.0% wt %, 1.31 mmol) in DMF (5 mL) wasadded tert-butyl 4-[4-(trifluoromethyl)anilino]piperidine-1-carboxylate(300 mg, 0.870 mmol) at 0° C. under nitrogen atmosphere. The mixture wasstirred at 0° C. for 15 min, and then iodomethane (371 mg, 2.61 mmol)was added. The reaction mixture was stirred at 80° C. for 12 hrs. Thereaction mixture was poured into water (20 mL) and extracted three timeswith EtOAc, the combined organic layers were washed twice with water andbrine, dried over sodium sulfate and concentrated in vacuum to affordlight yellow residue, which was purified by silica gel column elutingwith a gradient of PE:EtOAc (20:1 to 5:1) to give the desired product aswhite solid (160 mg, 51.3%). MS (ESI): m/z=303.1 [M−56+H]⁺.

BB93 N-methyl-N-(4-(trifluoromethyl)phenyl)azetidin-3-amine(Trifluoroacetic Acid Salt)

The title compound was prepared in analogy to method D6 from tert-butyl3-[N-methyl-4-(trifluoromethyl)anilino]azetidine-1-carboxylate (48%). MS(ESI): m/z=231.1 [M+H]⁺.

Step a) tert-Butyl 3-[4-(trifluoromethyl)anilino]azetidine-1-carboxylate

To a solution of p-trifluoromethylaniline (0.780 mL, 6.21 mmol, CAS RN455-14-1), AcOH (1.86 g, 31.0 mmol) and 1-BOC-3-azetidinone (2.13 g,12.4 mmol, CAS RN 398489-26-4) in EtOH (10 mL) was added NaBH₃CN (1.95g, 31.0 mmol) at 25° C. The mixture was stirred at 25° C. for 12 h. Thereaction mixture was poured into saturated aqueous NH₄Cl solution (20mL) and extracted twice with EtOAc. The combined organic layers werewashed twice with H₂O and brine, dried over sodium sulfate andconcentrated in vacuum to afford yellow residue, which was purified bysilica gel column eluting with a gradient of PE:EtOAc (10:1 to 5:1) togive the desired product as white solid (340 mg, 17.3%). MS (ESI):m/z=261.1 [M−56+H]⁺.

Step b) tert-Butyl3-[N-methyl-4-(trifluoromethyl)anilino]azetidine-1-carboxylate

To a solution of tert-butyl3-[4-(trifluoromethyl)anilino]azetidine-1-carboxylate (300 mg, 0.950mmol) in DMF (5 mL) was added NaH (45.5 mg, 60% wt %, 1.14 mmol) at 0°C. The mixture was stirred for 15 min, and then iodomethane (404 mg,2.85 mmol) was added. The reaction mixture was stirred at 25° C. for 12h. The reaction mixture was poured into H₂O (20 mL) and extracted twicewith EtOAc. The combined organic layers were washed three times with H₂Oand brine, dried over Na₂SO₄ and concentrated in vacuum to afford yellowresidue. The residue was purified by silica gel column eluting with agradient of PE:EtOAc (10:1 to 5:1) to give the desired product as whitesolid (310 mg, 98.9%). MS (ESI): m/z=275.2 [M−56+H]⁺.

Method D7 BB94N-methyl-N-(piperidin-4-yl)-2-(3-(trifluoromethyl)phenyl)acetamidehydrochloride

To a solution of tert-butyl4-[methyl-[2-[3-(trifluoromethyl)phenyl]acetyl]amino]piperidine-1-carboxylate(0.080 g, 200 μmol) in DCM (1 mL) was added a 2 M HCl solution indiethyl ether (999 μL, 2 mmol). The reaction mixture was stirred at RTovernight and then concentrated in vacuo to afford the title compound(67 mg, 199 μmol) as an off-white solid. MS (ESI): m/z=301.2 [M+H]⁺.

Step a) tert-Butyl4-[methyl-[2-[3-(trifluoromethyl)phenyl]acetyl]amino]piperidine-1-carboxylate

To a stirred mixture of 2-(3-(trifluoromethyl)phenyl)acetic acid (105mg, 513 μmol, CAS RN 351-35-9) in DMF (5 mL) was added HATU (195 mg, 513μmol) and DIPEA (181 mg, 244 μL, 1.4 mmol). After 15 min. stirring,tert-butyl 4-(methylamino)piperidine-1-carboxylate (0.100 g, 467 μmol,CAS RN 147539-41-1) was added and the reaction mixture was stirred at RTfor 2 h. The reaction mixture was diluted with DCM and washed with H₂O.The org. phase was concentrated to give a crude product which waspurified by flash chromatography on a 20 g SiO₂ column, using an eluentmixture of n-heptane and EtOAc (0% to 100%) to afford the desiredcompound as a light yellow oil (85 mg, 213 μmol). MS (ESI): m/z=459.259[M+CH₃CN+NH₄]⁺.

Method D8 BB194 3-(4-Chloro-3-cyclopropylphenoxy)azetidine

To a solution of tert-butyl3-(4-chloro-3-cyclopropylphenoxy)azetidine-1-carboxylate (0.023 g, 0.057mmol) in DCM (1 mL) was added TFA (0.088 mL, 1.14 mmol) and the reactionmixture stirred at room temperature for 18 hours. The mixture wasdiluted with DCM, poured into a sat. aq. NaHCO₃ solution and extractedwith DCM. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and evaporated to dryness to yield the crude titlecompound (0.007 g, 35%) as a colorless oil. MS (ESI): m/z=224.1 [M+H]⁺.

Step a) tert-Butyl 3-(3-bromo-4-chlorophenoxy)azetidine-1-carboxylate

In a sealed tube, 3-bromo-4-chlorophenol (0.1 mg, 0.482 mmol) andtert-butyl 3-hydroxyazetidine-1-carboxylate (0.083 g, 0.482 mmol) weredissolved in toluene (1.5 mL). The vial was degassed with argon, then(tributylphosphoranylidene)acetonitrile (CAS RN 157141-27-0, 0.195 mL,0.723 mmol) was added and the reaction mixture heated to 100° C. for 30minutes. The mixture was diluted with EtOAc, poured into sat. aq. NaHCO₃solution and the aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel flashchromatography eluting with a 0 to 20% EtOAc/heptane gradient to givethe title compound (0.116 g, 53%) as a yellow oil. MS (ESI): m/z=308.1[M−56+H]⁺.

Step b) tert-Butyl3-(4-chloro-3-cyclopropylphenoxy)azetidine-1-carboxylate

In a microwave vial, tert-butyl3-(3-bromo-4-chlorophenoxy)azetidine-1-carboxylate (0.075 g, 0.165mmol), cyclopropylboronic acid (0.021 g, 0.248 mmol) and K₂CO₃ (0.046 g,0.331 mmol) were mixed in dioxane (1.6 mL). Then, water (0.4 mL) wasadded followed by bis(triphenylphosphine)palladium (II) chloride (0.012g, 0.016 mmol) and the reaction mixture heated at 130° C. undermicrowave irradiation for 1 hour. The reaction mixture was diluted withEtOAc, poured into water and extracted with EtOAc. The organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica gel flash chromatography,eluting with a 0 to 10% EtOAc/heptane gradient to give the titlecompound (0.023 g, 43%) as a colorless oil. MS (ESI): m/z=268.2[M−56+H]⁺.

Method D9 BB197 3-(2-Chloro-3-cyclopropylphenoxy)azetidine,Trifluoroacetate Salt

To a solution of tert-butyl3-(2-chloro-3-cyclopropyl-phenoxy)azetidine-1-carboxylate (0.1 g, 0.310mmol) in DCM (2.5 mL) was added TFA (0.25 mL) and the reaction mixturewas stirred at room temperature for 2 hours. The mixture wasconcentrated in vacuo to give the crude title compound (0.083 g, 80%yield) as a dark brown oil. MS (ESI): m/z=224.6 [M+H]⁺.

Step a) tert-Butyl 3-(3-bromo-2-chloro-phenoxy)azetidine-1-carboxylate

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (0.5 g,2.89 mmol) and 3-bromo-2-chloro-phenol (0.5 g, 2.41 mmol) in THF (10 mL)were added PPh₃ (0.948 g, 3.62 mmol) followed by diethylazodicarboxylate (0.47 mL, 3.62 mmol) and the reaction mixture wasstirred at room temperature for 12 hours. The mixture was purified byreversed phase HPLC to give the title product (0.4 g, 46%) as a lightyellow oil. MS (ESI): m/z=308.3 [M−56+H]⁺.

Step b) tert-Butyl3-(2-chloro-3-cyclopropylphenoxy)azetidine-1-carboxylate

In a sealed tube, cyclopropylboronic acid (0.071 g, 0.830 mmol),tert-butyl 3-(3-bromo-2-chloro-phenoxy)azetidine-1-carboxylate (0.2 g,0.550 mmol) and Na₂CO₃ (0.117 g, 1.1 mmol) were mixed in 1,4-dioxane (5mL) and water (1 mL). Then, Pd(dppf)Cl₂ (0.040 g, 0.060 mmol) was addedand the mixture was stirred to 110° C. for 12 hours. The mixture waspurified by reversed phase HPLC to give the title compound (0.12 g, 67%)as a light yellow oil. MS (ESI): m/z=268.1 [M−56+H]⁺.

Method D10 BB202 5-(4-Piperidyloxy)-2-(trifluoromethyl)benzonitrile,Trifluoroacetate

To a solution of tert-butyl4-[3-cyano-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (0.05 g,0.140 mmol) in DCM (1.5 mL) was added TFA (0.2 mL) and the reactionmixture stirred at room temperature for 12 hours. The mixture wasconcentrated in vacuo to give the crude title compound (0.051 g, 98%) asa light brown oil. MS (ESI): m/z=271.6 [M+H]⁺.

Step a) tert-Butyl4-[3-bromo-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

To a solution of 3-bromo-4-(trifluoromethyl)phenol (0.5 g, 2.54 mmol)and 1-Boc-4-hydroxypiperidine (0.512 g, 2.54 mmol) in THF (8.5 mL) wereadded PPh₃ (1 g, 3.82 mmol) followed by diethyl azodicarboxylate (0.665g, 3.82 mmol) and the reaction mixture was stirred at room temperaturefor 12 hours. The mixture was purified by silica gel flashchromatography, eluting with with PE:EtOAc 5:1 to give the titlecompound (0.5 g, 47%) as a light yellow oil. MS (ESI): m/z=370.2[M−56+H]⁺.

Step b) tert-Butyl4-[3-cyano-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

In a sealed tube, tert-butyl4-[3-bromo-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (0.2 g,0.470 mmol), Zn(CN)₂ (0.111 g, 0.940 mmol), CuI (0.09 g, 0.470 mmol)were mixed in DMF (10 mL). Then, Pd(PPh₃)₄ (0.109 g, 0.090 mmol) wasadded and the reaction mixture stirred to 130° C. for 16 hours. Themixture was purified by reversed phase HPLC to give the title product(0.05 g, 29%) as a colorless oil. MS (ESI): m/z=315.5 [M−56+H]⁺.

Method E Example 263(+)-5-[1-[(4aR,8aS)-3-Oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]azetidin-3-yl]oxy-2-(trifluoromethyl)benzonitrile

In a sealed tube,(+)-(4aR,8aS)-6-[3-[3-bromo-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one(BB 205, 0.2 g, 0.420 mmol), Zn(CN)₂ (0.098 g, 0.840 mmol), Zn (0.027 g,0.420 mmol), dppf (0.232 g, 0.420 mmol), Hünig's base (0.108 g, 0.840mmol) were mixed in DMA (10 mL) and the mixture was degassed. Then,Pd₂(dba)₃ (76.59 mg, 0.080 mmol) was added and the reaction mixture wasstirred at 130° C. for 16 h. The mixture was purified by reversed phaseHPLC to give the title compound (0.055 g, 30%) as a light yellow solid.MS (ESI): m/z=425.3 [M+H]⁺.

Method F Example 265(+)-(4aR,8aS)-6-[3-[3-(2-Azaspiro[3.3]heptan-2-yl)-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

In a sealed tube,(+)-(4aR,8aS)-6-[3-[3-bromo-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one(BB203, 0.2 g, 0.420 mmol), 2-azaspiro[3.3]heptane (CAS RN 665-04-03,0.117 g, 0.630 mmol), BINAP (0.052 g, 0.080 mmol) and K₂CO₃ (0.173 g,1.25 mmol) were mixed in DMF (10 mL) and the mixture was degassed. Then,Pd₂(dba)₃ (76.59 mg, 0.080 mmol) was added and the reaction mixture wasstirred to 110° C. for 16 hours. The reaction mixture was filtered off,the filtrate diluted with water (50 mL) and extracted with EtOAc (3×20mL). Combined organics were washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by reversedphase HPLC to give the title compound (0.06 g, 29%) as a white solid. MS(ESI): m/z=495.1 [M+H]⁺.

Method G Example 293(4aR,8aS)-6-(3-(4-Hydroxy-2-(trifluoromethyl)phenethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Boron tribromide (11.3 mg, 4.29 μL, 45.3 μmol) was added to an icecooled solution of(4aR,8aS)-6-(3-(4-methoxy-2-(trifluoromethyl)phenethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one(Example 216, 20 mg, 45.3 μmol) in DCM (0.5 mL). The reaction mixturewas stirred at ambient temperature for 3 h. A saturated solution ofaqueous NaHCO₃was added and the mixture was extracted with AcOEt. Thelayers were separated, the organic layer was dried over Na₂SO₄, filteredand the solvent removed under reduced pressure. The crude product waspurified by prep. HPLC to give the title compound (19%) as colorlesssolid. MS (ESI): m/z=427.2 [M+H]⁺.

The following examples listed in the table below were prepared inanalogy to the procedure described for the preparation of Example 265 byusing the indicated intermediates and/or commercially availablecompounds and using the mentioned purification method such asreversed-phase HPLC or silica gel flash chromatography.

Ex Systematic Name/Structure Intermediates MS, m/z 266(+)-(4aR,8aS)-6-[3-[3-(3-Methylazetidin- BB203 BH66 469.2 l-yl)-4- and[M + H]⁺ (trifluoromethyl)phenoxy]azetidine-1- 3-Methylazetidinecarbonyl]-4,4a,5,7,8,8a- hydrochloridehexahydropyrido[4,3-b][l,4]oxazin-3-one (CAS RN 935669-28-6)

267 (+)-(4aR,8aS)-6-[3-[3-(3,3- BB203 491.2 Difluoroazetidin-1 -yl)-4-and [M + H]⁺ (trifluoromethyl)phenoxy]azetidine-1 - Difluoroazetidinecarbonyl]-4,4a,5,7,8,8a- hydrochloridehexahydropyrido[4,3-b][l,4]oxazin-3-one (CAS RN 288315-03-7)

268 (+)-(4aR,8aS)-6-[3-[3-(3-Fluoro-3-methyl- BB203 487.3azetidin-1-yl)-4- and [M + H]⁺ (trifluoromethyl)phenoxy]azetidine-1-3-Fluoro-3-methyl- carbonyl]-4,4a,5,7,8,8a- azetidine hydrochloridehexahydropyrido[4,3-b][l,4]oxazin-3-one (CAS RN 1427379-42-7)

269 (+)-(4aR,8aS)-6-[3-[3-(6,6-Difluoro-2- BB203 531.1azaspiro[3.3]heptan-2-yl)-4- and [M + H]⁺(trifluoromethyl)phenoxy]azetidine-1- 6,6-Difluoro-2-carbonyl]-4,4a,5,7,8,8a- azaspiro[3.3]heptanehexahydropyrido[4,3-b][l,4]oxazin-3-one (CAS RN 1354952-05-8)

270 (+)-(4aR,8aS)-6-[3-[3-(5-oxa-2- BB203 525.3azaspiro[3.5]nonan-2-yl)-4- and [M + H]⁺(trifluoromethyl)phenoxy]azetidine-1- 5-Oxa-2- carbonyl]-4,4a,5,7,8,8a-azaspiro[3.5]nonane hexahydropyrido[4,3-b][l,4]oxazin-3-one (CAS RN138387-19-6)

271 (+)-(4aR,8aS)-6-[3-[3-(2- Example 258 461.1Azaspiro[3.3]heptan-2-yl)-2-chloro- and [M + H]⁺phenoxy]azetidine-1-carbonyl]- 2-Azaspiro[3.3]heptane4,4a,5,7,8,8a-hexahydropyrido[4,3- (CAS RN 665-04-03)b][1,4]oxazin-3-one

272 (+)-(4aR,8aS)-6-[3-[2-Chloro-3-(3- Example 258 435.1methylazetidin-1-yl)phenoxy]azetidine-1- and [M + H]⁺carbonyl]-4,4a,5,7,8,8a- 3-Methylazetidinehexahydropyrido[4,3-b][l,4]oxazin-3-one hydrochloride (CAS RN935669-28-6)

273 (+)-(4aR,8aS)-6-[3-[2-Chloro-3-(3-fluoro-3- Example 258 453.2methyl-azetidin-1-yl)phenoxy]azetidine-1- and [M + H]⁺carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- 3-Fluoro-3-methyl- b] [1,4]oxazin-3-one azetidine hydrochloride (CAS RN 1427379-42-7)

274 (+)-(4aR,8aS)-6-(3-(3-(3-(tert- Example 258 493.2Butoxy)azetidin-1-yl)-2- and [M + H]⁺ chlorophenoxy)azetidine-1-3-tert-Butoxyazetidine carbonyl)hexahydro-2H-pyrido[4,3- (CAS RN1147530-63-9) b][1,4]oxazin-3(4H)-one

275 (+)-(4aR,8aS)-6-[3-[2-Chloro-3-(5-oxa-2- Example 258 477.2azaspiro[3.4]octan-2- and [M + H]⁺ yl)phenoxy]azetidine-1-carbonyl]-5-Oxa-2- 4,4a,5,7,8,8a-hexahydropyrido[4,3- azaspiro[3.4]octaneb][1,4]oxazin-3-one (CAS RN 145309-24-6)

276 (+)-(4aR,8aS)-6-[3-[2-chloro-3-(5-oxa-2- Example 258 491.2azaspiro[3.5]nonan-2- and [M + H]⁺ yl)phenoxy]azetidine-1-carbonyl]-5-Oxa-2- 4,4a,5,7,8,8a-hexahydropyrido[4,3- azaspiro[3.5]nonaneb][1,4]oxazin-3-one (CAS RN 138387-19-6)

277 (+)-(4aR,8aS)-6-[3-[3-(2- BB204 461.3Azaspiro[3.3]heptan-2-yl)-5-chloro- and [M + H]⁺phenoxy]azetidine-1-carbonyl]- 2-Azaspiro[3.3]heptane4,4a,5,7,8,8a-hexahydropyrido[4,3- (CAS RN 665-04-03)b][1,4]oxazin-3-one

278 (+)-(4aR,8aS)-6-[3-(3-Chloro-5-pyrrolidin- BB204 435.3l-yl-phenoxy)azetidine-1-carbonyl]- and [M + H]⁺4,4a,5,7,8,8a-hexahydropyrido[4,3- Pyrrolidine b][1,4]oxazin-3-one

In analogy to the methods described herein above, the following buildingblocks were prepared from the respective starting material indicated inthe table below.

BB No. Systematic Name Starting material Method MS, m/z BB47 3-[(2-tert-Butyl 3-[(2- D3 212.1 Chlorophenoxy)methyl]pyrrolidine;chlorophenoxy)methyl]pyrrolidine-1- [M + H]⁺ hydrochloride saltcarboxylate BB47a BB48 4-[[2-Fluoro-4- tert-Butyl 4-[[2-fluoro-4- D2262.1 (trifluoromethyl)phenyl]methyl]piperidine:(trifluoromethyl)phenyl]methyl]piperidine-1- [M + H]⁺ formic acid saltcarboxylate BB48a BB49 3-[(2- tert-Butyl 3-[(2- D3 212.1Chlorophenyl)methoxy]pyrrolidine; chlorophenyl)methoxy]pyrrolidine-1-[M + H]⁺ hydrochloride salt carboxylate BB49a BB50 3-[(3- tert-Butyl3-[(3- D3 212.1 Chlorophenyl)methoxy]pyrrolidine;chlorophenyl)methoxy]pyrrolidine-1- [M + H]⁺ hydrochloride saltcarboxylate BB50a BB52 3-[(4- tert-Butyl 3-[(4- D3 212.1Chlorophenoxy)methyl]pyrrolidine; chlorophenoxy)methyl]pyrrolidine-1-[M + H]⁺ hydrochloride salt carboxylate BB52a BB53 3-[(4- tert-Butyl3-[(4- D2 Used Chlorophenyl)methoxy]pyrrolidinechlorophenyl)methoxy]pyrrolidine-1- without formic acid salt carboxylatefurther BB53a purification BB54 4-[[2-Methyl-4- tert-Butyl4-[[2-methyl-4- D2 258.2 (trifluoromethyl)phenyl](trifluoromethyl)phenyl]methyl]piperidine-1- [M + H]⁺ methyl]piperidine; formic carboxylate acid salt BB54a BB55 4-[[2-Chloro-4-tert-Butyl 4-[[2-chloro-4- D1 278.0 (trifluoromethyl)phenyl]me-(trifluoromethyl)phenyl]methyl]piperidine-1- [M + H]⁺ thyl]piperidine;trifluoroacetate carboxylate salt BB55a BB71 4-[4-Chloro-3- tert-Butyl4-[4-chloro-3- D3 280.0 (trifluoromethyl)phenoxy]piperidine;(trifluoromethyl)phenoxy]piperidine-1- [M + H]⁺ hydrochloride saltcarboxylate BB71a BB72 4-(4-Chloro-3-cyclopropyl- tert-Butyl4-(4-chloro-3- D1 Used phenoxy) piperidine; cyclopropyl- withouttrifluoroacetate salt phenoxy)piperidine-1- further carboxylate BB72apurification BB73 4-[2-Chloro-5-(4- tert-Butyl 4-(4-chloro-3- D3 Usedpiperidyloxy) phenyl] morpholino- without morpholine hydrochloridephenoxy)piperidine-1- further carboxylate purification BB73a BB744-[2-Methyl-4- tert-Butyl 4-[2-methyl-4- D1 260.2(trifluoromethyl)phenoxy]piperidine;(trifluoromethyl)phenoxy]piperidine-1- [M + H]⁺ trifluoroacetate saltcarboxylate BB74a BB75 2-(4-Piperidyloxy)-5- tert-Butyl 4-[2-cyano-4- D4271.1 (trifluoromethyl)benzonitrile(trifluoromethyl)phenoxy]piperidine-1- [M + H]⁺ carboxylate BB75a BB762-(4- tert-Butyl 4-(oxazolo[5,4- D1 218.1 Piperidylmethyl)oxazolo[5,4-c]pyridin-2- [M + H]⁺ c]pyridine; trifluoroacetateylmethyl)piperidine-1- salt carboxylate BB76a BB89 3-[(3- tert-Butyl3-[(3- D3 212.1 Chlorophenoxy)methyl]pyrrolidine;chlorophenoxy)methyl]pyrrolidine-1- [M + H]⁺ hydrochloride saltcarboxylate BB89a BB192 4-[2-Fluoro-4- tert-Butyl 4- D3 264.2(trifluoromethyl)phenoxy]piperidine; hydroxypiperidine-1- [M + H]⁺hydrochloride salt carboxylate BB193 4-[3-Chloro-4- tert-Butyl4-[3-chloro-4- D3 280.1 (trifluoromethyl)phenoxy]piperidine;(trifluoromethyl)phenoxy]piperidine-1- [M + H]⁺ hydrochloride saltcarboxylate BB195 4-[2-Chloro-3- tert-Butyl 4-[2-chloro-3- D8 280.1(trifluoromethyl)phenoxy]piperidine;(trifluoromethyl)phenoxy]piperidine-1- [M + H]⁺ hydrochloride saltcarboxylate BB196 3-(3-Bromo-2-chloro- tert-Butyl 3-(3-bromo-2- D1 263.0phenoxy)azetidine; chloro-phenoxy)azetidine-1- [M + H]⁺ trifluoroacetatesalt carboxylate BB198 3-[3-Bromo-4- tert-Butyl 3-[3-bromo-4- D9 296.4(trifluoromethyl)phenoxy]azetidine;(trifluoromethyl)phenoxy]azetidine-1- [M + H]⁺ trifluoroacetate saltcarboxylate BB199 3-[3-Cyclopropyl-4- tert-Butyl 3-[3-cyclopropyl-4- D9258.1 (trifluoromethyl)phenoxy]azetidine;(trifluoromethyl)phenoxy]azetidine-1- [M + H]⁺ trifluoroacetate saltcarboxylate BB200 3-[3-Chloro-4- tert-Butyl 3-[3-chloro-4- D1 252.5(trifluoromethyl)phenoxy]azetidine;(trifluoromethyl)phenoxy]azetidine-1- [M + H]⁺ trifluoroacetate saltcarboxylate BB201 3-(3-Bromo-5-chloro- tert-Butyl 3-(3-bromo-5- D1 263.9phenoxy)azetidine; chloro-phenoxy)azetidine-1- [M + H]⁺ trifluoroacetatesalt carboxylate BB205 3-(3-Bromo-4-chloro- tert-Butyl 3-(3-bromo-4- D1263.9 phenoxy)azetidine; chlorophenoxy)azetidine-1- [M + H]⁺trifluoroacetate salt carboxylate

BB91 4-[[2-Pyrrolidin-1-yl-4-(trifluoromethyl)phenyl]methyl]piperidine;Formic Acid Salt

A solution of tert-butyl4-[[2-pyrrolidin-1-yl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate(500 mg, 1.21 mmol) in 6 M HCl in MeOH solution (10.0 mL) was stirred at20° C. for 1 h. The mixture was concentrated under vacuum, purified byreversed phase column to give the title compound as an orange oil (84.4mg, 21.8% yield). MS (ESI): m/z=313.2 [M+H]⁺.

Step a) Tert-butyl4-[[2-pyrrolidin-1-yl-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate

To a solution of tert-butyl4-[[2-bromo-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate(800 mg, 1.90 mmol; BB51, step c), pyrrolidine (163 mg, 2.28 mmol),Ruphos (4.25 mg, 0.010 mmol) and potassium tert-butoxide (320 mg, 2.86mmol) in toluene (15 mL) was added palladium(II) acetate (1.28 mg, 0.010mmol). The mixture was stirred at 80° C. for 15 h under N₂ atmosphere.The mixture was filtered and concentrated under vacuum to removetoluene. The mixture was diluted with H₂O (40 mL) and extracted threetimes with EtOAc (40 mL each). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated. The residuewas purified by silica gel chromatography (PE/EtOAc=1:0 to 8:1) to givethe compound as light yellow oil (552 mg, 1.34 mmol, 36.7%) MS (ESI):m/z=411.1 [M+H]⁺.

Step b) Tert-butyl4-[[2-pyrrolidin-1-yl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate

To a solution of tert-butyl4-[[2-pyrrolidin-1-yl-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate(525 mg, 0.660 mmol) in MeOH (20 mL) was added wet Pd/C (˜52 mg) and themixture was stirred at 20° C. under H₂ atmosphere (balloon) for 1 h. Themixture was filtered and concentrated under vacuum to give the desiredcompound as colorless oil (500 mg) which was used in the next stepwithout further purification.

BB95 3-[2-[2-fluoro-6-(trifluoromethyl)phenyl]ethyl]azetidine4-methylbenzenesulfonate

To an solution of3-[2-[2-fluoro-6-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate(50 mg, 144 μmol, Eq: 1) in EtOAc (0.8 mL) was added4-methylbenzenesulfonic acid monohydrate (29.7 mg, 173 μmol, Eq: 1.2)and the mixture was heated at reflux for 1.5 hours. The clear, colorlesssolution was allowed to cool down to RT. No precipitation occured. Thesolution was evaporated to give the desired product as a colorless foam.MS (ESI): m/z=248.1 [M−TsOH+H]+.

Step a) tert-butyl3-[(E)-2-[2-fluoro-6-(trifluoromethyl)phenyl]ethenyl]azetidine-1-carboxylate

To an ice-cold solution of diethyl(2-fluoro-4-(trifluoromethyl)benzyl)phosphonate (300 mg, 955 μmol) inTHF (2 mL) was added sodium hydride 55% in mineral oil (41.7 mg, 955μmol) and the mixture was stirred at this temperature for 30 minutes. Tothe light brown mixture was added dropwise a solution of tert-butyl3-formylazetidine-1-carboxylate (177 mg, 955 μmol) in THF (1 mL). Thisled to an immediate discoloration of the reaction mixture. Stirring wascontinued for 1 hours at ice-bath temperature followed by stirring at RTfor 1.5 hours. The reaction mixture was poured into water and ethylacetate and the layers were separated. The aqueous layer was extractedtwice with ethyl acetate. The organic layers were washed once withbrine, dried over MgSO₄, filtered, treated with silica gel andevaporated. The compound was purified by silica gel chromatography on a12 g column using an MPLC system eluting with a gradient ofn-heptane:ethyl acetate (100:0 to 25:75) to get the desired compound asa colorless solid (0.108 g; 32.8%). MS (ESI): m/z=290.2 [M−56+H]+.

Step b) tert-butyl3-[2-[2-fluoro-6-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate

To a solution of tert-butyl(E)-3-(2-fluoro-4-(trifluoromethyl)styryl)azetidine-1-carboxylate (105mg, 304 μmol) in MeOH (1 mL) and Ethyl acetate (1 mL) was added Pd/C 10%(11 mg, 304 μmol) and the mixture was stirred under a hydrogenatmosphere at 1.7 bar and RT for 30 minutes. The suspension wasfiltered. The filtrate was evaporated to get the desired compound as acolorless oil (0.104 g; 98.5%). MS (ESI): m/z=292.2 [M−56+H]+.

BB96 4-((2-chloro-4-fluorophenoxy)methyl)azepane hydrochloride

To a solution of tert-butyl4-((2-chloro-4-fluorophenoxy)methyl)azepane-1-carboxylate (620 mg, 1.73mmol) in DCM (7.5 ml) was added HCl in ether 2M (10 ml, 20 mmol) and thereaction mixture was stirred overnight at rt. The mixture wasconcentrated in vacuo, the crude material collected as a white solid(490 mg, 1.67 mmol, 96.1%) and used directly on the next step. LC-MS(ESI): m/z: 258.2 [M+H]+

Step a) tert-butyl4-((2-chloro-4-fluorophenoxy)methyl)azepane-1-carboxylate

In a 25 ml four-necked sulphonation flask under argon, tert-butyl4-(hydroxymethyl)azepane-1-carboxylate (480 mg, 2.09 mmol) was dissolvedin THF (10 ml). Subsequently, 2-chloro-4-fluorophenol (337 mg, 251 μl,2.3 mmol) and triphenylphosphine (604 mg, 2.3 mmol) were added and theclear solution was stirred for 5 min at rt. The mixture was cooled to 0°C. and DEAD (401 mg, 365 μl, 2.3 mmol) was added in portions over 10min. The mixture was stirred for 1 hr at 0° C., then overnight at rt.The mixture was taken up into EtOAc (50 ml), washed with water (2×25ml), organic phase washed with 1M NaOH (3×25 ml), brine (20 ml), driedwith Na₂SO₄, filtered and concentrated in vacuo. Residue was dissolvedin n-Heptane/diethylether and the mixture stirred for 30 min, the TPPOprecipitate filtered and the crude concentrated in vacuo. The crudematerial was adsorbed on Isolute® and purified by flash columnchromatography (0-30% EtOAc/Heptane) over silica gel (50 g) to affordthe desired product (630 mg, 1.76 mmol, 84.1%) as a yellow oil. LC-MS(ESI): m/z: 302.1 [M−56+H]+

BB97 4-[[4-(trifluoromethyl)phenyl]methyl]azepane hydrochloride

To a solution of tert-butyl4-(4-(trifluoromethyl)benzyl)azepane-1-carboxylate (88 mg, 246 μmol,Eq: 1) in DCM (1.5 ml) was added HCl in ether 2M (3.08 ml, 6.16 mmol)and the reaction mixture was stirred overnight at room temperature. Themixture was concentrated in vacuo, the crude material collected as awhite solid (71 mg, 0.24 mmol, 98.2%) and used directly on the nextstep. LC-MS (ESI): m/z: 258.2 [M+H]+

Step a: Triphenyl(4-(trifluoromethyl)benzyl)phosphonium bromide

Triphenylphosphine (1.84 g, 7 mmol) and1-(bromomethyl)-4-(trifluoromethyl)benzene (1.61 g, 6.74 mmol) weredissolved in xylene (35 ml). The reaction mixture was heated to refluxat 155° C. for 3.5 h and then cooled to room temperature. Theprecipitated white crystalline solid was collected by filtration, washedwith diethyl ether and dried in vacuo. The final compound (3.30 g, 6.58mmol, 97.7% yield) was obtained as a white powder and directly used onthe next step. LC-MS (ESI): m/z: 421.2 [M+H]+

Step b: tert-butyl(E)-4-(4-(trifluoromethyl)benzylidene)azepane-1-carboxylate

A suspension of sodium hydride (88.6 mg, 2.22 mmol) in DMF (7.5 ml) wascooled in an ice bath, thentriphenyl(4-(trifluoromethyl)benzyl)phosphonium bromide (1.11 g, 2.22mmol) was added. The suspension was stirred at 0° C. for 5 min. then for25 min at rt. tert-butyl 4-oxoazepane-1-carboxylate (315 mg, 1.48 mmol)was added and the resulting mixture was stirred at 80° C. for 28 h. Themixture was concentrated in vacuo, diluted with water (50 ml) and EtOAc(40 ml) and extracted EtOAc (3×30 ml). The combined organic fractionswere washed with water, 10% LiCl solution, dried with Na₂SO₄ andconcentrated in vacuo. The residual oil was treated with Et2O in orderto precipitate the triphenylphosphoxide that was filtered off. Thesolution was concentrated in vacuo and the residue was purified by flashcolumn chromatography (0-35% EtOAc/Heptane) over silica gel (50 g) toafford the desired product (92 mg, 259 μmol, 17.5% yield) as a yellowoil. LC-MS (ESI): m/z: 300.2 [M−56+H]+

Step c: tert-butyl 4-(4-(trifluoromethyl)benzyl)azepane-1-carboxylate

A solution of tert-butyl(E)-4-(4-(trifluoromethyl)benzylidene)azepane-1-carboxylate (90 mg, 253μmol) was dissolved in MeOH (2.5 ml). The reaction vessel was evacuatedand back-filled with argon 5 times. Under argon, Pd—C (13.5 mg, 12.7μmol) was added and the atmosphere was replaced with hydrogen threetimes. The reaction was stirred under a hydrogen atmosphere at 1 bar for24 h. The atmosphere was replaced with argon and the reaction mixturewas filtered over a pad of Dicalite. The filter cake was washed withmethanol. The filtrate was concentrated in vacuo to give the desiredproduct (89 mg, 249 μmol, 98.3% yield) as a colorless oil which was usedwithout further purification. LC-MS (ESI): m/z: 302.2 [M−56+H]+

BB98 3-((2-Chloro-4-(trifluoromethyl)phenyl)thio)azetidine2,2,2-trifluoroacetate

tert-Butyl3-((2-chloro-4-(trifluoromethyl)phenyl)thio)azetidine-1-carboxylate (110mg, 299 μmol) was dissolved in DCM (2 mL) and TFA (273 mg, 184 μL, 2.39mmol) was added. The reaction mixture was stirred at RT for 3 h.Volatiles were removed in vacuo to yield 110 mg of a light yellow solid(96%). MS (ESI): m/z=268.1 [M+H]⁺.

Step a) tert-Butyl3-((2-chloro-4-(trifluoromethyl)phenyl)thio)azetidine-1-carboxylate

In a 20 mL glastube, a solution of2-chloro-4-(trifluoromethyl)benzenethiol (440 mg, 2.07 mmol) in dry THF(6 mL) was added potassium tert-butoxide 1M solution in THF (2.17 ml,2.17 mmol) and the yellow reaction mixture was stirred at RT for 15 minfollowed by addition of tert-butyl 3-bromoazetidine-1-carboxylate (489mg, 2.07 mmol). The reaction mixture was then stirred at RT for 5 h andover night at 70° C. The crude reaction was diluted with EtOAc andextracted with H₂O, the organic phase was collected and the aqueousphase was back-extracted with EtOAc. The combined organic phases weredried over Na₂SO₄ and evaporated down to dryness. The residue waspurified by chromatography (SiO₂, n-eptane/EtOAc (0 to 40% over 40 min)yielded the product as a viscous oil (467 mg, 61%). MS (ESI): m/z=312.1[M-56]⁺.

BB99 3-((2-Chloro-4-(trifluoromethyl)phenyl)sulfonyl)azetidine2,2,2-trifluoroacetate

tert-Butyl3-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)azetidine-1-carboxylate(100 mg, 250 μmol) was dissolved in DCM and TFA (228 mg, 154 μL, 2 mmol)was added. The reaction mixture was stirred at RT for 8 h. Volatileswere removed in vacuo to yield the desired compound as light yellowsolid (102 mg, 98%). MS (ESI): m/z=300.0 [M+H]⁺.

Step a) tert-Butyl3-((2-chloro-4-(trifluoromethyl)phenyl)thio)azetidine-1-carboxylate

In a 20 mL glastube, a solution of2-chloro-4-(trifluoromethyl)benzenethiol (440 mg, 2.07 mmol) in dry THF(6 mL) was added potassium tert-butoxide 1M solution in THF (2.17 mL,2.17 mmol) and the yellow reaction mixture was stirred at r.t for 15 minfollowed by addition of tert-butyl 3-bromoazetidine-1-carboxylate (489mg, 2.07 mmol). The reaction mixture was then stirred at r.t for 5 h andover night at 70° C. The crude reaction was diluted with EtOAc andextracted with H₂O, the organic phase was collected and the aqueousphase was back-extracted with EtOAc. The combined organic phases weredried over Na₂SO₄ and evaporated down to dryness. The residue waspurified by column chromatography (SiO₂, n-eptane/EtOAc (0 to 40% over40 min) to yield the desired product as a viscous oil (467 mg, 61%). MS(ESI): m/z=312.1 [M−56+H]⁺.

Step b) tert-Butyl3-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)azetidine-1-carboxylate

mCPBA (347 mg, 1.41 mmol) was added in one portion to a stirred solutionof tert-butyl3-((2-chloro-4-(trifluoromethyl)phenyl)thio)azetidine-1-carboxylate (345mg, 938 μmol) in DCM (6 mL) in an ice bath. The reaction was stirred atRT for 20 min. The reaction mixture was poured into 5 mL saturatedNa₂CO₃ solution and extracted twice with DCM (20 mL each). The organiclayers were combined, washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The crude material was purified by preparativeHPLC (YMC-Triart C18, ACN/H2O+0.1% HCOOH) to furnish the product as awhite powder (253 mg, 67.5%) MS (ESI): m/z=344.0 [M-56+H]⁺.

BB100 3-((2-Chloro-4-(trifluoromethyl)phenyl)sulfinyl)azetidine2,2,2-trifluoroacetate

tert-Butyl3-((2-chloro-4-(trifluoromethyl)phenyl)sulfinyl)azetidine-1-carboxylate(50 mg, 130 μmol) was dissolved in DCM (1.5 mL), TFA (149 mg, 100 μL,1.3 mmol) was added and the reaction mixture was stirred at RT for 8 h.Volatiles were removed in vacuo to yield the compound as white solid (51mg, 98%). MS (ESI): m/z=284.1 [M+H]⁺.

Step a) tert-Butyl3-((2-chloro-4-(trifluoromethyl)phenyl)thio)azetidine-1-carboxylate

The compound was prepared in analogy to BB99, step a, and used in thenext step without further purification.

Step b) tert-Butyl3-((2-chloro-4-(trifluoromethyl)phenyl)sulfinyl)azetidine-1-carboxylate

The sulfoxide intermediate was isolated from the the synthesis of theaccording sulfone building block BB99, step b. The product was obtainedas a white lyophilized powder (50 mg, 13.9%) MS (ESI): m/z=328.1[M−56+H]⁺.

BB101 3-(((2-Chloro-4-(trifluoromethyl)phenyl)thio)methyl)azetidine2,2,2-trifluoroacetate

To a solution of tert-butyl3-(((2-chloro-4-(trifluoromethyl)phenyl)thio)methyl)azetidine-1-carboxylate(0.200 g, 524 μmol) in DCM (3 mL) was added TFA (478 mg, 323 μL, 4.19mmol) and the reaction mixture was stirred at RT for 3 h. Volatiles wereremoved in vacuo to yield the compound as light yellow oil that was usedin the next step without further purification (267 mg). MS (ESI):m/z=282.2 [M+H]⁺.

Step a) tert-Butyl3-[[2-chloro-4-(trifluoromethyl)phenyl]sulfanylmethyl]azetidine-1-carboxylate

To a solution of 2-chloro-4-(trifluoromethyl)benzenethiol (0.400 g, 1.88mmol) in dry THF (6 mL) was added potassium tert-butoxide 1M solution inTHF (1.98 mL, 1.98 mmol) and the turbid reaction mixture was stirred atRT for 15 min followed by addition of tert-butyl3-(bromomethyl)azetidine-1-carboxylate (471 mg, 1.88 mmol). The reactionmixture was then stirred at RT for 19 h. The crude reaction was dilutedwith EtOAc and extracted with aq. 1 M NaHCO₃ solution, the organic phasewas collected and the aqueous phase was back-extracted with EtOAc. Thecombined organic phases were dried over Na₂SO₄ and evaporated down todryness to yield the crude product which was used in the next stepwithout further purification (762 mg). MS (ESI): m/z=326.1 [M−56+H]⁺.

BB102 3-((2-Fluoro-6-(trifluoromethyl)benzyl)sulfonyl)azetidine2,2,2-trifluoroacetate

tert-Butyl3-((2-fluoro-6-(trifluoromethyl)phenyl)methylsulfonyl)azetidine-1-carboxylate(0.047 g, 118 μmol) was dissolved in DCM (0.5 mL) and TFA (108 mg, 72.9μL, 946 μmol) was added. The reaction mixture was stirred at RT for 2 h.Volatiles were removed in vacuo to yield the compound as a yellow oil(56 mg) that was used in the next step without further purification. MS(ESI): m/z=298.2 [M+H]⁺.

Step a) tert-Butyl3-((2-fluoro-6-(trifluoromethyl)benzyl)thio)azetidine-1-carboxylate

To a solution of tert-butyl 3-mercaptoazetidine-1-carboxylate (0.400 g,2.11 mmol) in dry THF (5 mL) was added potassium tert-butoxide 1Msolution in THF (2.22 mL, 2.22 mmol) and the reaction mixture wasstirred at RT for 15 min followed by addition of2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene (CAS RN239087-08-2). The reaction mixture was then stirred at RT for 14 h. Thecrude reaction was diluted with EtOAc and extracted with aq. 1 MNaHCO₃solution, the organic phase was collected and the aqueous phasewas back-extracted with EtOAc. The combined organic phases were driedover NaSO₄ and evaporated down to dryness to yield the crude product(805 mg) which was used in the next step without further purification.MS (ESI): m/z=310.2 [M−56+H]⁺.

Step b) tert-Butyl3-[[2-fluoro-6-(trifluoromethyl)phenyl]methylsulfonyl]azetidine-1-carboxylate

3-Chlorobenzoperoxoic acid (283 mg, 1.64 mmol) was added in portion to astirred solution of tert-butyl3-((2-fluoro-6-(trifluoromethyl)benzyl)thio)azetidine-1-carboxylate(0.300 g, 821 μmol) in DCM (5 mL) in an ice bath. The reaction mixturewas stirred at RT for 15 min and poured into 5 mL saturated aqueousNaHCO₃solution and extracted twice with DCM (10 mL each). The organiclayers were combined, washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The crude material was purified by flash columnchromatography (silica gel, 20 g, 0% to 100% EtOAc in n-heptane) tofurnish the desired product as a colorless oil (47 mg, 15%). MS (ESI):m/z=415.1 [M+NH₄]⁺.

BB103 3-((2-Fluoro-6-(trifluoromethyl)benzyl)sulfinyl)azetidine2,2,2-trifluoroacetate

tert-Butyl3-[[2-fluoro-6-(trifluoromethyl)phenyl]methylsulfinyl]azetidine-1-carboxylate(0.086 g, 225 μmol) was dissolved in DCM (1 mL) and TFA (206 mg, 139 μL,1.8 mmol) was added. The reaction mixture was stirred at RT for 2 h.Volatiles were removed in vacuo to yield the compound as a yellow oil(93 mg) that was used in the next step without further purification. MS(ESI): m/z=282.2 [M+H]⁺.

Step a) tert-Butyl3-[[2-fluoro-6-(trifluoromethyl)phenyl]methylsulfinyl]azetidine-1-carboxylate

The sulfoxide intermediate was isolated from the synthesis of BB102,step b, as a colorless oil (86 mg, 28%). MS (ESI): m/z=404.1 [M+Na]⁺.

BB104 3-(((2-Chloro-4-(trifluoromethyl)phenyl)sulfonyl)methyl)azetidine2,2,2-trifluoroacetate

tert-Butyl3-(((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)methyl)azetidine-1-carboxylate(0.145 g, 350 μmol) was dissolved in DCM (2 mL) and TFA (320 mg, 216 μL,2.8 mmol) was added. The reaction mixture was stirred at RT for 2 h.Volatiles were removed in vacuo to yield the compound as a yellow oil(181 mg) that was used in the next step without further purification. MS(ESI): m/z=314.1 [M+H]⁺.

Step a) tert-Butyl3-(((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)methyl)azetidine-1-carboxylate

3-Chlorobenzoperoxoic acid (352 mg, 1.57 mmol) was added in portions toa stirred solution of tert-butyl3-(((2-chloro-4-(trifluoromethyl)phenyl)thio)methyl)azetidine-1-carboxylate(BB101, step a) (0.300 g, 786 μmol) in DCM (5 mL) in an ice bath. Thereaction mixture was stirred at RT for 15 min and poured into 5 mLsaturated aqueous NaHCO₃ solution and extracted twice with DCM (10 mLeach). The organic layers were combined, washed with brine, dried overNa₂SO₄ and concentrated in vacuo. The crude material was purified byflash chromatography (silica gel, 20 g, 0% to 100% EtOAc in n-heptane)to provide the desired product as a colorless oil (145 mg, 45%). MS(ESI): m/z=314.0 [M−56+H]⁺.

BB105 3-(((2-Chloro-4-(trifluoromethyl)phenyl)sulfinyl)methyl)azetidine2,2,2-trifluoroacetate

tert-Butyl3-(((2-chloro-4-(trifluoromethyl)phenyl)sulfinyl)methyl)azetidine-1-carboxylate(0.086 g, 216 μmol) was dissolved in DCM (1 mL) and TFA (197 mg, 133 μL,1.73 mmol) was added. The reaction mixture was stirred at RT for 2 h.Volatiles were removed in vacuo to yield the compound as a yellow oil(99 mg) that was used in the next step without further purification. MS(ESI): m/z=298.1 [M+H]⁺.

Step a) tert-Butyl3-(((2-chloro-4-(trifluoromethyl)phenyl)sulfinyl)methyl)azetidine-1-carboxylate

The sulfoxide intermediate was isolated from the synthesis of BB104,step a. The desired product was obtained as a yellow oil (80 mg, 25.6%).MS (ESI): m/z=398.1 [M+H]⁺.

BB106 3-((2-Fluoro-4-(trifluoromethyl)benzyl)thio)azetidine2,2,2-trifluoroacetate

To a solution of tert-butyl3-((2-fluoro-4-(trifluoromethyl)benzyl)thio)azetidine-1-carboxylate(0.282 g, 772 μmol) in DCM (3 mL) was added TFA (880 mg, 595 μL, 7.72mmol) and the reaction mixture was stirred at RT for 3 h. Volatiles wereremoved in vacuo to yield the desired compound as a colorless oil (302mg) that was used in the next step without further purification. MS(ESI): m/z=266.2 [M+H]⁺.

Step a) tert-Butyl3-[[2-fluoro-4-(trifluoromethyl)phenyl]methylsulfanyl]azetidine-1-carboxylate

To a solution of tert-butyl 3-mercaptoazetidine-1-carboxylate (0.200 g,1.06 mmol) in dry THF (2 mL) was added potassium tert-butoxide 1Msolution in THF (1.11 mL, 1.11 mmol) and the reaction mixture wasstirred at RT for 15 m followed by addition of1-(bromomethyl)-2-fluoro-4-(trifluoromethyl)benzene (272 mg, 1.06 mmol,CAS RN 239087-07-1). The reaction mixture was then stirred at RT for 14h. The crude reaction was diluted with EtOAc and extracted with aq. 1 MNaHCO₃ solution, the organic phase was collected and the aqueous phasewas back-extracted with EtOAc. The combined organic phases were driedover NaSO₄ and evaporated down to dryness and purified by flashchromatography (silica gel, 20 g, 000 to 80% EtOAc in n-heptane) tofurnish the desired product as a colorless oil (288 mg, 75%). MS (ESI):m/z=310.2 [M−56+H].

In analogy to BB184, the following intermediates were prepared from therespective commercially available starting materials.

BB No. Systematic Name Starting material MS, m/z BB107 3-[2-(2,6-1,3-Dichloro-2-iodobenzene 226.1 Dichlorophenyl)ethynyl]azetidine [M +H]⁺ BB108 3-[2-[2-Fluoro-4- 1-Bromo-2-fluoro-4- 244.2(trifluoromethyl)phenyl]ethynyl]azetidine (trifluoromethyl)benzene [M +H]⁺ BB109 3-[2-(2,6- 1,3-Difluoro-2-iodobenzene 194.2Difluorophenyl)ethynyl]azetidine [M + H]⁺ BB110 3-[2-[3-Chloro-4-4-Bromo-2-chloro-1- 260.2 (trifluoromethyl)phenyl]ethynyl]azetidine(trifluoromethyl)benzene [M + H]⁺ BB111 3-[2-(2-Chloro-6-fluoro-2-Bromo-1-chloro-3- 210.1 phenyl)ethynyl]azetidine fluorobenzene [M +H]⁺ BB112 3-[2-(2-Chloro-4-cyclopropyl- 1-Bromo-2-chloro-4- 232.2phenyl)ethynyl]azetidine cyclopropylbenzene [M + H]⁺ BB113 3-[2-(2-1-Bromo-2-methoxybenzene 188.2 Methoxyphenyl)ethynyl]azetidine [M + H]⁺BB114 3-[2-[4-Chloro-2- 4-Chloro-1-iodo-2- 260.1(trifluoromethyl)phenyl]ethynyl]azetidine (trifluoromethyl)benzene [M +H]⁺ BB115 3-[2-(3-Chlorophenyl)ethynyl]azetidine 1-Bromo-3-chlorobenzene192.1 [M + H]⁺ BB116 3-[2-[4- 1-bromo-4- 242.2(Trifluoromethoxy)phenyl]ethynyl]azetidine (Trifluoromethoxy)benzene[M + H]⁺ BB117 3-[2-[4- 1-Bromo-4- 226.2(Trifluoromethyl)phenyl]ethynyl]azetidine (trifluoromethyl)benzene [M +H]⁺ BB118 3-[2-(3-Fluoro-2-methyl- 1-Bromo-3-fluoro-2- 190.2phenyl)ethynyl]azetidine methylbenzene [M + H]⁺ BB119 3-[2-(2,6-2-Iodo-1,3-dimethylbenzene 186.2 Dimethylphenyl)ethynyl]azetidine [M +H]⁺ BB120 3-[2-[2- 1-Bromo-2- 242.2(Trifluoromethoxy)phenyl]ethynyl]azetidine (trifluoromethoxy)benzene[M + H]⁺ BB121 3-[2-(2-Bromophenyl)ethynyl]azetidine1-Bromo-2-iodobenzene 236.1 [M + H]⁺ BB122 3-[2-(2-Chloro-3-fluoro-1-Bromo-2-chloro-3- 210.1 phenyl)ethynyl]azetidine fluorobenzene [M +H]⁺ BB123 3-[2-(o-Tolyl)ethynyl]azetidine 1-Bromo-2-methylbenzene 172.2[M + H]⁺ BB124 3-[2-(4-Chloro-2-fluoro- 4-Chloro-2-fluoro-1- 210.1phenyl)ethynyl]azetidine iodobenzene [M + H]⁺ BB125 3-[2-[2-1-(Difluoromethoxy)-2- 224.2 (Difluoromethoxy)phenyl]ethynyl]azetidineiodobenzene [M + H]⁺ BB126 2-[2-(Azetidin-3-yl)ethynyl]-3-chloro-2-Bromo-3- 217.2 benzonitrile chlorobenzonitrile [M + H]⁺ BB127 3-[2-[4-1-(Difluoromethoxy)-4- 224.2 (Difluoromethoxy)phenyl]ethynyl]azetidineiodobenzene [M + H]⁺ BB128 1-[4-[2-(Azetidin-3- 1-(4- 223.2yl)ethynyl]phenyl]cyclopropanecarbonitrile Bromophenyl)cyclopropane-[M + H]⁺ 1-carbonitrile BB129 3-[2-(4-Cyclopropylphenyl)prop-1-1-Bromo-4-cyclopropyl- 198.2 ynyl]azetidine benzene [M + H]⁺ BB1301-[4-[2-(Azetidin-3- 1-(4- 214.2 yl)ethynyl]phenyl]cyclopropanolBromophenyl)cyclopropanol [M + H]⁺ BB131 3-[2-(3-1-Iodo-3-methoxybenzene 188.2 Methoxyphenyl)ethynyl]azetidine [M + H]⁺BB132 3-[2-[2- 1-Bromo-2- 208.2 (Difluoromethyl)phenyl]ethynyl]azetidine(difluoromethyl)benzene [M + H]⁺ BB133 3-[2-(3-Methoxy-2-methyl-1-Iodo-3-methoxy-2- 202.2 phenyl)ethynyl]azetidine methylbenzene [M +H]⁺ BB134 3-[2-(2-Chloro-6-methyl- l-Chloro-2-iodo-3- 206.1phenyl)ethynyl]azetidine methylbenzene [M + H]⁺ BB1353-[2-(2-Chloro-5-fluoro- 2-Bromo-1-chloro-4- 210.1phenyl)ethynyl]azetidine fluorobenzene [M + H]⁺ BB136 3-[2-(4-1-Bromo-4-methylsulfonyl- 236.2 Methylsulfonylphenyl)ethynyl]azetidinebenzene [M + H]⁺ BB137 3-[2-(5-Chloro-2- 2-Bromo-5-chlorothiophene 198.1thienyl)ethynyl]azetidine [M + H]⁺ BB138 3-[2-(5-Chloro-3-4-Bromo-2-chlorothiophene 198.1 thienyl)ethynyl]azetidine [M + H]⁺ BB1393-[2-[2-Chloro-6-fluoro-4- 2-Bromo-1-chloro-3-fluoro- 278.1(trifluoromethyl)phenyl]ethynyl]azetidine 5-(trifluoromethyl)benzene[M + H]⁺ BB140 3-[2-(2-Chlorophenyl)ethynyl]azetidin-Chloro-2-iodobenzene 208.1 3-ol and [M + H]⁺ tert-butyl 3-ethynyl-3-hydroxyazetidine-1- carboxylate (CAS RN 1259034-35-9) BB141 3-[2-[2-1-Iodo-2- 202.2 (Methoxymethyl)phenyl]ethynyl]azetidine(methoxymethyl)benzene [M + H]⁺ BB142 3-[2-[2-Chloro-4-2-Chloro-1-iodo-4- 260.2 (trifluoromethyl)phenyl]ethynyl]azetidine(trifluoromethyl)benzene [M + H]⁺

In analogy to BB 18, the following intermediates were prepared from therespective commercially available starting materials.

BB No. Systematic Name Starting material MS, m/z BB143 4-[2-[2-1-Bromo-2- 254.3 (Trifluoromethyl)phenyl]ethynyl]piperidine(trifluoromethyl)benzene [M + H]⁺ BB144 4-[2-(2-1-Bromo-2-methoxybenzene 216.3 Methoxyphenyl)ethynyl]piperidine [M + H]⁺BB145 4-[2-(o-Tolyl)ethynyl]piperidine 1-Bromo-2-methylbenzene 200.3[M + H]⁺ BB146 4-[2-(2,6- 2-Iodo-1,3-dimethylbenzene 214.3Dimethylphenyl)ethynyl]piperidine [M + H]⁺ BB1474-[2-(2,4-Dichlorophenyl)ethynyl]-4- Bromo-2,4-dichlorobenzene 268.2methyl-piperidine and [M + H]⁺ tert-Butyl 4-ethynyl-4-methylpiperidine-1- carboxylate (CAS RN 1363383-17-8) BB1484-[2-(2-Chloro-4-fluoro- 2-Chloro-4-fluoro-1- 252.2phenyl)ethynyl]-4-methyl-piperidine iodobenzene [M + H]⁺ and tert-Butyl4-ethynyl-4- methylpiperidine-1- carboxylate (CAS RN 1363383-17-8)

BB149 1-[2-(Azetidin-3-yl)ethynyl]cyclopentanol hydrochloride

To a solution of tert-butyl3-[2-(1-hydroxycyclopentyl)ethynyl]azetidine-1-carboxylate (0.02 g,0.075 mmol) in dioxane (0.5 mL) was added 4 M HCl in dioxane (0.094 mL,0.377 mmol) and the reaction mixture was stirred at RT for 18 h. Themixture was evaporated to dryness and the residue triturated indiisopropyl ether, filtered off and further dried under high vacuum togive the title compound as a white solid as the hydrochloride salt(0.013 g, 87%). MS (ESI): m/z=166.1 [M+H]⁺.

Step a) tert-Butyl3-[2-(1-hydroxycyclopentyl)ethynyl]azetidine-1-carboxylate

To a solution of tert-butyl 3-ethynylazetidine-1-carboxylate (0.2 g, 1.1mmol) in THF (6.5 mL) at −78° C. was added nBuLi (0.759 mL, 1.21 mmol)dropwise and the reaction mixture was stirred at this temperature for 1h. Then, cyclopentanone (0.107 mL, 1.21 mmol) in THF (3 mL) was addeddropwise to the mixture which was stirred at −78° C. for 2 h. Themixture was allowed to warm up to 0° C., poured into a sat. NH₄OHaqueous solution and extracted with EtOAc. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and evaporated. Theresidue was purified by silica gel flash chromatography, eluting with agradient of EtOAc n-heptane (0 to 100%) to yield the title compound as alight yellow oil (0.020 g, 7%). MS (ESI): m/z=192.2 [M-56-18+H]⁺.

BB150 4-[3-Pyrazol-1-yl-5-(trifluoromethyl)phenoxy]piperidine formate

A mixture of tert-butyl4-[3-pyrazol-1-yl-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate(400.0 mg, 0.970 mmol) and TFA (1.0 mL, 0.970 mmol) in DCM (10 mL) wasstirred at 20° C. for 12 h. The mixture was purified by prep-HPLC (ACNand water containing 0.225% v/v FA) to give the desired product (300 mg,94.4%) as colorless gum. MS (ESI): m/z=312.1 [M+H]⁺.

Step a: tert-Butyl4-[3-bromo-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

To a solution of 3-bromo-5-(trifluoromethyl)phenol (2.0 g, 8.3 mmol),1-BOC-4-hydroxypiperidine (1.84 g, 9.13 mmol, CAS RN 106-52-5) and PPh₃(2.61 g, 9.96 mmol) in THF (32.6 mL) was added diisopropylazodicarboxylate (1.96 mL, 9.96 mmol) and the mixture was stirred at 20°C. for 15 h. The mixture was concentrated under vacuum. The residue waspurified by prep-HPLC (ACN and water containing 0.225% v/v FA) andconcentrated under vacuum to give the desired product (2.6 g, 73.9%yield) as light yellow oil. MS (ESI): m/z=367.9 [M−56+H]⁺.

Step b) tert-Butyl4-[3-pyrazol-1-yl-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

A mixture of tert-butyl4-[3-bromo-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (500.0mg, 1.18 mmol), pyrazole (160.47 mg, 2.36 mmol), CuI (22.37 mg, 0.120mmol), cesium carbonate (1152 mg, 3.54 mmol) andN,N′-dimethylethylenediamine (519.15 mg, 5.89 mmol) in DMF (5 mL) wasstirred at 110° C. for 12 h. The mixture was poured into H₂O water (30mL) and extracted three times with EtOAc (50 mL). The combined organiclayer was washed with ammonia (10 mL), brine (50 mL), dried over Na₂SO₄and filtered. The filtrate was concentrated under vacuum to give thedesired product (400 mg, 82.5% yield) as light yellow oil. MS (ESI):m/z=356.2 [M-56+H]⁺.

BB1514-[[2-(2,2,2-Trifluoroethoxy)-4-(trifluoromethyl)phenyl]methyl]piperidine

A mixture of4-[[2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl]methylene]piperidine(250.0 mg, 0.740 mmol) and Pd/C (50.0 mg, wt.10%) in THF (10 mL) wasstirred at 20° C. for 12 h under H₂ (1520 mmHg). The mixture wasfiltered and concentrated under vacuum to give the desired compound (240mg, 95.4%) as light brown gum. MS (ESI): m/z=342.1 [M+H]⁺.

Step a) tert-Butyl 4-(p-tolylsulfonylhydrazono)piperidine-1-carboxylate

To a solution of 4-methylbenzenesulfonhydrazide (9.35 g, 50.19 mmol, CASRN 1576-35-8) in MeOH (100 mL) was added 1-BOC-4-piperidone (10.0 g,50.19 mmol, CAS RN 17502-28-8) and the mixture was stirred at 25° C. for12 h. The mixture was concentrated to give the desired product (18.4 g,99.8%) as off-white solid. MS (ESI): m/z=368.2 [M+H]⁺.

Step b) 2-(2,2,2-Trifluoroethoxy)-4-(trifluoromethyl)benzaldehyde

A mixture of NaH (187.39 mg, 60% dispersion in mineral oil, 4.68 mmol,)in 2,2,2-trifluoroethanol (16.67 mL, 228.74 mmol, CAS RN75-89-8) wasstirred at 0° C. The cooling bath was removed and the mixture wasstirred at 20° C. for 2 h, and then2-fluoro-4-(trifluoromethyl)benzaldehyde (1.0 g, 5.21 mmol, CAS RN763-93-9) was added and the mixture was stirred at 20° C. for 12 h. Themixture was poured into H2O (30 mL) and extracted twice with EtOAc (30mL each). The combined organic layers were washed with brine (30 mL),dried over Na₂SO₄ and filtered. The filtrate was concentrated undervacuum to give the desired product (1.2 g, 84.7%) as light yellow solid.¹H NMR (400 MHz, DMSO-d6) δ 10.44-10.34 (m, 1H), 7.93 (d, J=8.1 Hz, 1H),7.75 (s, 1H), 7.55 (d, J=8.1 Hz, 1H), 5.11 (q, J=8.7 Hz, 2H).

Step c) tert-Butyl4-[2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)benzoyl]piperidine-1-carboxylate

A mixture of 2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)benzaldehyde(1000.0 mg, 3.67 mmol), tert-butyl4-(p-tolylsulfonylhydrazono)piperidine-1-carboxylate (1350.3 mg, 3.67mmol) and cesium carbonate (1795.9 mg, 5.51 mmol) in 1,4-dioxane (30 mL)was stirred at 110° C. for 12 h under N₂ atmosphere. The mixture waspoured into H2O (50 mL) and extracted three times with EtOAc (50 mLeach). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄ and filtered. The filtrate was concentrated under vacuum andthe residue was purified by prep-HPLC (MeCN and water containing 0.225%v/v FA) to give the desired product (980 mg, 58.6%) as light yellow gum.MS (ESI): m/z=400.1 [M−56+H]⁺.

Step d) tert-Butyl4-[hydroxy-[2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate

To a solution of tert-butyl4-[2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)benzoyl]piperidine-1-carboxylate(900.0 mg, 1.98 mmol) in MeOH (45 mL) was added NaBH₄ (149.54 mg, 3.95mmol) at 0° C. and the mixture was stirred at 20° C. for 12 h. Themixture was purified by prep-HPLC (MeCN and water containing 0.225% v/vFA) (650 mg, 71.9%) as light yellow oil. MS (ESI): m/z=384.0[M-56-OH+H]⁺.

Step e)4-[[2-(2,2,2-Trifluoroethoxy)-4-(trifluoromethyl)phenyl]methylene]piperidine

A mixture of tert-butyl4-[hydroxy-[2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate(400.0 mg, 0.870 mmol) and MsOH (840.43 mg, 8.74 mmol) in DCM (4 mL) wasstirred at 40° C. for 24 h. The mixture was poured into saturatedaqueous Na₂CO₃ solution (5 mL) and extracted three times with EtOAc (10mL each). The combined organic layers were washed with brine (10 mL),dried over Na₂SO₄ and filtered. The filtrate was concentrated undervacuum to give the desired compound as light yellow oil (260 mg, 76.2%).MS (ESI): m/z=340.1 [M+H]⁺.

BB152 4-[3-(1,2,4-Triazol-1-yl)-5-(trifluoromethyl)phenoxy]piperidinetrifluoroacetate

To a mixture of tert-butyl4-[3-(1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate(240.0 mg, 0.580 mmol) in DCM (10 mL) was added TFA (1.0 mL). Themixture was stirred at 20° C. for 12 h and then concentrated undervacuum to give4-[3-(1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenoxy]piperidine2,2,2-trifluoroacetic acid salt (240 mg, 96.7%) as light yellow gum. MS(ESI): m/z=313.1 [M+H]⁺.

Step a) tert-Butyl4-[3-(1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

A mixture of tert-butyl4-[3-bromo-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (500.0mg, 1.18 mmol, BB98, intermediate a), 1,2,4-triazole (162.8 mg, 2.36mmol) and CuI (22.37 mg, 0.120 mmol) in DMF (5 mL) was stirred at 110°C. for 12 h. The mixture was poured into H2O (20 mL) and extracted threetimes with EtOAc (30 mL each). The combined organic layers were washedwith ammonia (20 mL), brine (20 mL, three times), dried over Na₂SO₄ andfiltered. The filtrate was concentrated under vacuum and the residue waspurified by column chromatography (PE:EA=50:1 ˜3:1) to give the desiredproduct (240 mg, 49.4%) as light yellow solid. MS (ESI): m/z=357.1[M-56+H]⁺.

BB153 3-[4-Chloro-3-(trifluoromethyl)phenoxy]azetidine trifluoroacetate

To a solution of tert-butyl3-[4-chloro-3-(trifluoromethyl)phenoxy]azetidine-1-carboxylate (300.0mg, 0.530 mmol) in DCM (7.5 mL) was added TFA (1.04 mL) at 0° C. and themixture was stirred at 20° C. for 2 h. The mixture was concentrated togive the title compound as yellow oil (280 mg, 97%). MS (ESI): m/z=252.0[M+H]⁺.

Step a) tert-Butyl3-[4-chloro-3-(trifluoromethyl)phenoxy]azetidine-1-carboxylate

To a solution of 2-chloro-5-hydroxybenzotrifluoride (1 g, 5.1 mmol CASRN 6294-93-5), tert-butyl 3-hydroxyazetidine-1-carboxylate (0.97 g, 5.6mmol CAS RN 141699-55-0) and triphenylphosphine (1.6 g, 6.11 mmol) inTHF (20 mL) was added diisopropyl azodicarboxylate (1.2 mL, 6.11 mmol)and the mixture was stirred at 20° C. for 15 h. The mixture wasconcentrated and purified by reversed phase chromatography (MeCN andwater containing 0.225% v/v FA) to give the title compound (820 mg,28.7%) as brown solid. MS (ESI): m/z=295.9 [M−56+H]⁺.

BB154 4-(4-Chloro-3-pyrazol-1-yl-phenoxy)piperidine trifluoroacetate

To a solution of tert-butyl4-(4-chloro-3-pyrazol-1-yl-phenoxy)piperidine-1-carboxylate (260.0 mg,0.690 mmol) in DCM (5.38 mL) was added TFA (1.34 mL, 17.46 mmol) at 0°C. and the mixture was stirred at 20° C. for 1 h. The mixture wasconcentrated to give the title compound as an orange oil (250 mg, 92.7yield). MS (ESI): m/z=278.1 [M+H]⁺.

Step a) tert-Butyl 4-(3-bromo-4-chloro-phenoxy)piperidine-1-carboxylate

To a solution of 1-BOC-4-hydroxypiperidine (2.04 g, 10.12 mmol, CAS RN106-52-5), 3-bromo-4-chlorophenol (2.0 g, 9.64 mmol, CAS RN 2402-82-6)and triphenylphosphine (3.03 g, 11.57 mmol) in THF (50 mL) was addeddiisopropyl azodicarboxylate (2.28 mL, 11.57 mmol) and the mixture wasstirred at 20° C. for 15 h. Then the mixture was concentrated and theresidue was purified by reversed flash chromatography (MeCN and watercontaining 0.1% v/v FA) to give the desired product (2.8 g, 74.3%) aslight yellow oil. MS (ESI): m/z=335.9 [M−56+H]⁺.

Step b) tert-Butyl4-(4-chloro-3-pyrazol-1-yl-phenoxy)piperidine-1-carboxylate

To a mixture of tert-butyl4-(3-bromo-4-chloro-phenoxy)piperidine-1-carboxylate (1.0 g, 2.56 mmol),pyrazole (139.4 mg, 2.05 mmol), cesium carbonate (2501.8 mg, 7.68 mmol)and 1,10-phenanthroline (225.49 mg, 2.56 mmol) in DMF (20 mL) was addedCuI (48.59 mg, 0.260 mmol) and the mixture was stirred at 110° C. for 12h under N₂ atmosphere. The mixture was concentrated, diluted with H2O(20 mL) and extracted three times with EtOAc (10 mL). The combinedorganic layers were concentrated and the residue purified by reversedphase chromatography (ACN and water containing 0.1% v/v FA) to give thedesired product (265 mg, 22.5%, 82% purity) as yellow oil. MS (ESI):m/z=378.1 [M+H]⁺.

BB155 4-[5-(4-Piperidyloxy)-2-(trifluoromethyl)phenyl]morpholinetrifluoroacetate

To a solution of tert-butyl4-[3-morpholino-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate(400.0 mg, 0.93 mmol) in DCM (3 mL) was added TFA (1.0 mL) and thereaction mixture was stirred at 25° C. for 12 h. The reaction wasconcentrated in vacuum to provide the crude product (300 mg) as yellowoil, which was used in next step without further purification. MS (ESI):m/z=331.2 [M+H]⁺.

Step a) tert-Butyl4-(3-bromo-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate

To a solution of 3-bromo-4-(trifluoromethyl)phenol (500.0 mg, 2.54 mmol,CAS RN1214385-56-4) and 1-BOC-4-hydroxypiperidine (512 mg, 2.54 mmol,CAS RN 106-52-5) in THF (8.5 mL) was added PPh3 (1000.9 mg, 3.82 mmol)and diethyl azodicarboxylate (664.53 mg, 3.82 mmol) and the mixture wasstirred at 25° C. for 12 h. The mixture was purified by silica gelchromatography using PE:EA=5:1 as eluant to provide the desired product(503 mg, 46.6% yield) as light yellow oil. MS (ESI): m/z=369.2 [M−56+H].

Step b) tert-Butyl4-(3-morpholino-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate

A mixture of tert-butyl4-[3-bromo-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (500.0mg, 1.18 mmol), morpholine (154 mg, 1.77 mmol, CAS RN 110-91-8),(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (146.77 mg, 0.24mmol, CAS RN 76189-55-4), cesium carbonate (1.15 g, 3.54 mmol) andtris(dibenzylideneacetone)dipalladium(0) (172.47 mg, 0.240 mmol, CAS RN76971-72-7) in DMF (10 mL) was stirred at 110° C. for 12 h. The mixturewas poured into H2O and extracted three times with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄ and filtered.The filtrate was concentrated under vacuum and the residue was purifiedby column chromatography (gradient of EtOAc in PE 5% to 33%) to give thedesired product (480 mg, 94.6%) as light yellow solid. MS (ESI):m/z=431.1 [M+H]⁺.

BB156 4-(4-Chloro-3-(1,2,4-triazol-1-yl)phenoxy)piperidinetrifluoroacetate

To a solution of tert-butyl4-[4-chloro-3-(1,2,4-triazol-1-yl)phenoxy]piperidine-1-carboxylate(196.0 mg, 0.520 mmol) in DCM (5 mL) was added TFA (1.01 mL, 13.13 mmol)at 0° C. and the mixture was stirred at 20° C. for 1 h. The mixture wasconcentrated to give the title compound (178 mg, 87.6%) as brown oil. MS(ESI): m/z=279.1 [M+H]⁺.

Step a) tert-Butyl4-[4-chloro-3-(1,2,4-triazol-1-yl)phenoxy]piperidine-1-carboxylate

A mixture of tert-butyl4-(3-bromo-4-chloro-phenoxy)piperidine-1-carboxylate (500.0 mg, 1.28mmol, BB102, intermediate a), 1,2,4-triazole (176.8 mg, 2.56 mmol), CuI(24.3 mg, 0.130 mmol) and cesium carbonate (1250.9 mg, 3.84 mmol) anddimethyl glycine (1.0 mL, 1.28 mmol) in DMF (10 mL) was stirred at 120°C. for 12 h. The mixture was concentrated to remove the DMF, dilutedwith H2O (50 mL) and extracted three times with EtOAc (20 mL each). Thecombined organic layers were evaporated and the residue purified byreverse phase flash chromatography (ACN and water containing 0.1% v/vFA) to give the title compound (196 mg, 37.1%) as colorless oil. MS(ESI): m/z=323.0 [M−56+H]⁺.

BB157 4-[3-Cyclopropyl-4-(trifluoromethyl)phenoxy]piperidinetrifluoroacetate

To a mixture of tert-butyl4-[3-cyclopropyl-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate(360.0 mg, 0.930 mmol) in DCM (18 mL) was added TFA (1.8 mL). Themixture was stirred at 25° C. for 12 h. The mixture was concentratedunder vacuum to provide the desired compound as light yellow gum (370mg, 99.2%). MS (ESI): m/z=286.2 [M+H]⁺.

Step a) tert-Butyl4-[3-cyclopropyl-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

A mixture of tert-butyl4-[3-bromo-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (500.0mg, 1.18 mmol, BB103, intermediate b), cyclopropylboronic acid (151.86mg, 1.77 mmol), Na₂CO₃ (374.74 mg, 3.54 mmol) and Pd(PPh3)4 (13.6 mg,0.010 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL) was stirred at 95° C.for 12 h. The mixture was poured into H2O (50 mL) and extracted threetimes with EtOAc (50 mL each). The combined organic layers were washedwith brine (50 mL), dried over Na₂SO₄ and filtered. The filtrate wasconcentrated under vacuum and purified by column chromatography(PE:EtOAc=20:1˜5:1) to give the desired product (380 mg, 83.7%) ascolorless gum. MS (ESI): m/z=330.1 [M−56+H]⁺.

BB158 4-[3-Pyrazol-1-yl-4-(trifluoromethyl)phenoxy]piperidinetrifluoroacetate

To a solution of tert-butyl4-[3-pyrazol-1-yl-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate(180.0 mg, 0.440 mmol) in DCM (5 mL) was added TFA (0.5 mL). The mixturewas stirred at 25° C. for 12 h and then concentrated under vacuum togive the desired product (180 mg, 96.7%) as light yellow gum. MS (ESI):m/z=312.1 [M+H]⁺.

Step a) tert-Butyl4-[3-pyrazol-1-yl-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

A mixture of tert-butyl4-[3-bromo-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (500.0mg, 1.18 mmol, BB103, intermediate b), pyrazole (120.35 mg, 1.77 mmol),CuI (22.37 mg, 0.120 mmol), N,N′-dimethylethylenediamine (519.45 mg,5.89 mmol) and Cs₂CO₃ (767.99 mg, 2.36 mmol) in DMF (10 mL) was stirredat 110° C. for 12 h. The mixture was poured into H2O (30 mL) andextracted three times with EtOAc (50 mL each). The combined organiclayers were washed with ammonia (20 mL), brine (50 mL), dried overNa₂SO₄ and filtered. The filtrate was concentrated and the crude productwas purified by prep-TLC (PE:EA=5:1) to give the desired product (190mg, 39.2%) as colorless oil. MS (ESI): m/z=356.1 [M−56+H]⁺.

BB159 4-[[2,6-Difluoro-4-(trifluoromethyl)phenyl]methyl]piperidinetrifluoroacetate

To a solution of tert-butyl4-[[2,6-difluoro-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate(70.0 mg, 0.180 mmol) in DCM (1 mL) was added TFA (0.2 mL) and themixture was stirred at 20° C. for 1 h. The mixture was concentrated togive the title compound (50 mg, 68.9%) as brown oil. MS (ESI): m/z=280.1[M+H]⁺.

Step a)2-(Diethoxyphosphorylmethyl)-1,3-difluoro-5-(trifluoromethyl)benzene

A solution of 2-(bromomethyl)-1,3-difluoro-5-(trifluoromethyl)benzene(1.29 mL, 3.27 mmol, CAS RN 493038-91-8) in triethyl phosphite (5.44 g,32.73 mmol) was stirred at 160° C. for 5 h. The mixture was concentratedunder vacuum to provide the title compound (600 mg, 55.2%; colorlessoil) which was used in the next step without further purification.

Step b) tert-Butyl4-[[2,6-difluoro-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate

A mixture of2-(diethoxyphosphorylmethyl)-1,3-difluoro-5-(trifluoromethyl)benzene(400.0 mg, 1.2 mmol) in THF (4 mL) was added to sodium hydride (144.49mg, 3.61 mmol) in THF (4 mL) at 0° C. The mixture was stirred at 0° C.for 1 h, and then 1-BOC-4-piperidone (479.83 mg, 2.41 mmol, CAS RN79099-07-3) was added to the above mixture. The mixture was stirred at20° C. for 12 h. The mixture was poured into H2O (50 mL) and extractedthree times with EtOAc (20 mL each). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by column chromatography (PE:EA=1:0 to2:1) to give the title compound (100 mg, 22.0%) as colorless oil. MS(ESI): m/z=322.0 [M−56+H]⁺.

Step c) tert-Butyl4-[[2,6-difluoro-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate

To a solution of tert-butyl4-[[2,6-difluoro-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate(100.0 mg, 0.270 mmol) in MeOH (8 mL) was added Pd/C (10.0 mg, wt.10%).The mixture was stirred at 20° C. for 1 h under H2 atmosphere, thenfiltered and concentrated to give the title compound as colorless oil(70 mg, 69.6%). MS (ESI): m/z=324.1[M−56+H]⁺.

BB160 4-[4-Chloro-3-(4-chlorophenyl)-2-fluoro-phenoxy]piperidinetrifluoroacetate

To a mixture of tert-butyl4-[4-chloro-3-(4-chlorophenyl)-2-fluoro-phenoxy]piperidine-1-carboxylate(145.0 mg, 0.330 mmol) in DCM (10 mL) was added TFA (1.0 mL). Themixture was stirred at 20° C. for 5 h. The mixture was concentratedunder vacuum to give the desired product (149 mg, 99.6%) as light browngum. MS (ESI): m/z=340.1 [M+H]⁺.

Step a) 1-Chloro-2-(4-chlorophenyl)-3-fluoro-4-methoxy-benzene

A mixture of 4-bromochlorobenzene (1.41 g, 7.34 mmol, CAS RN 106-39-8),(6-chloro-2-fluoro-3-methoxy-phenyl) boronic acid (1.0 g, 4.89 mmol, CASRN 867333-04-8) and K₂CO₃ (2.03 g, 14.68 mmol) in 1,4-dioxane (15 mL)and H2O (1.5 mL) was stirred under N2 atmosphere at 110° C. for 1 h in amicrowave oven. The mixture was poured into H2O (20 mL) and extractedthree times with EtOAc (20 mL each). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄ and filtered. The filtratewas concentrated under vacuum and the residue was purified by columnchromatography using PE as eluant to give the desired product (110 mg,8.3%) as colorless oil which was used in the next step without furtherpurification.

Step b) 4-chloro-3-(4-chlorophenyl)-2-fluoro-phenol

To a mixture of 1-chloro-2-(4-chlorophenyl)-3-fluoro-4-methoxy-benzene(215.0 mg, 0.790 mmol) in DCM (7 mL) was added a solution of BBr3(993.36 mg, 3.97 mmol) in DCM (7 mL) drop wise at −78° C. The mixturewas stirred at 20° C. for 12 h. The reaction was quenched by adding MeOH(1 mL) followed by water (10 mL), and the mixture was extracted threetimes with DCM (10 mL each). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄ and filtered. The filtrate wasconcentrated under vacuum to give the desired product (120 mg, 57.5%) aslight brown solid which was used in the next step without furtherpurification.

Step c) tert-Butyl4-[4-chloro-3-(4-chlorophenyl)-2-fluoro-phenoxy]piperidine-1-carboxylate

A mixture of 4-chloro-3-(4-chlorophenyl)-2-fluoro-phenol (120.0 mg,0.470 mmol), 1-BOC-4-hydroxypiperidine (187.88 mg, 0.930 mmol, CAS RN106-52-5), PPh3 (244.85 mg, 0.930 mmol) and DIAD (0.18 mL, 0.930 mmol)in THF (12 mL) was stirred at 20° C. for 12 h. The mixture was pouredinto H2O and extracted three times with EtOAc. The combined organiclayer was washed with brine, dried over Na₂SO₄ and filtered. Thefiltrate was concentrated under vacuum and the residue purified bycolumn chromatography (PE:EA=1:0˜20:1) to give the desired product aslight yellow gum (150 mg, 73%). MS (ESI): m/z=384.0 [M−56+H]⁺.

BB161 3-[2-Chloro-4-(Trifluoromethyl)phenoxy]azetidine trifluoroacetate

To a solution of tert-butyl3-[2-chloro-4-(trifluoromethyl)phenoxy]azetidine-1-carboxylate (400.0mg, 1.14 mmol) in DCM (10 mL) was added TFA (2.0 mL) at 20° C. Afterstirring for 2 h the mixture was concentrated to give the crude product(410 mg, 98.6%) as light yellow oil which was used in the next stepwithout further purification.

Step a) tert-Butyl3-[2-chloro-4-(trifluoromethyl)phenoxy]azetidine-1-carboxylate

To a solution of 2-chloro-4-(trifluoromethyl)phenol (1000.0 mg, 5.09mmol, CAS RN 35852-58-5) and tert-butyl 3-hydroxyazetidine-1-carboxylate(1057.5 mg, 6.11 mmol, CAS RN 141699-55-0) in THF (20 mL) was added PPh3(1999.49 mg, 7.63 mmol) and diethyl azodicarboxylate (1329.05 mg, 7.63mmol), the mixture was stirred at 25° C. for 12 h. The reaction mixturesolution was evaporated in vacuum, the residue was purified byreverse-phase flash flash (0.1% v/v FA) to afford the desired product(800 mg, 2.27 mmol, 44.7% yield) as light yellow oil. MS (ESI):m/z=296.0 [M−56+H]⁺.

BB162 3-((2-Fluoro-6-(trifluoromethyl)benzyl)oxy)azetidinetrifluoroacetate

To a solution of tert-butyl3-[[2-fluoro-6-(trifluoromethyl)phenyl]methoxy]azetidine-1-carboxylate(400.0 mg, 1.15 mmol) in dry DCM (10 mL) was added TFA (2.0 mL) at 25°C. and the mixture was stirred at 25° C. for 12 h. The solvent wasstripped off and the residue was dried under vacuum to afford thedesired compound as yellow oil (300 mg, 22%). MS (ESI): m/z=250.0[M+H]⁺.

Step a) tert-Butyl3-[[2-fluoro-6-(trifluoromethyl)phenyl]methoxy]azetidine-1-carboxylate

To a solution of 2-fluoro-6-(trifluoromethyl)benzyl bromide (1000.0 mg,3.89 mmol, CAS RN 239087-08-2) and tert-butyl3-hydroxyazetidine-1-carboxylate (673.92 mg, 3.89 mmol, CAS RN141699-55-0) in dry THF (10 mL) at 25° C., was added t-BuOK (5.84 mL,5.84 mmol; 1.0 M in dry THF) and the mixture was stirred at 25° C. for12 h. The mixture was poured into H2O (10 mL) and extracted three timeswith EA (20 mL each). The combined organic layers were combined, driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated underreduced pressure, purified by flash chromatography on silica gel(gradient PE:EA=10:1 to 2:8) to give the title compound as colorless oil(1100 mg, 80.9%). MS (ESI): m/z=294.0 [M−56+H]⁺.

BB163 3-[2-(2-Fluoro-4-methyl-phenyl)ethyl]azetidine trifluoroacetate

To a solution of tert-butyl3-[2-(2-fluoro-4-methyl-phenyl)ethyl]azetidine-1-carboxylate (350.0 mg,1.19 mmol) in dry DCM (10 mL) at 25° C., was added TFA (1.0 mL, 1.19mmol) and the mixture was stirred at 25° C. for 12 h. The reactionmixture was concentrated by reduced pressure and the residue was driedin vacuum to provide the desired compound as colorless oil (260 mg,70.9%). MS (ESI): m/z=194.0 [M+H]⁺.

Step a) tert-Butyl 3-(2-trimethylsilylethynyl)azetidine-1-carboxylate

To a solution of trimethylsilylacetylene (9.97 g, 101.55 mmol, CAS RN1066-54-2) in dry THF (200 mL) at 25° C., was added i-PrMgCl (48.57 mL,97.14 mmol; 1.0 M in dry THF) and the mixture was stirred at 25° C. for15 mins. Then a solution of 1-BOC-3-iodoazetidine (25.0 g, 88.3 mmol,CAS RN 254454-54-1) was added followed by FeCl2 (0.34 g, 2.65 mmol) indry DMF (606 mL) and the mixture was stirred at 25° C. for 12 hrs. Themixture was poured into saturated aq. NH4Cl solution (200 mL) andextracted three times with EtOAc (150 mL each). The organic layers werecombined, dried with anhydrous Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel (PE:EA=20:1 to 10:1) to give the desiredproduct as black oil (18 g, 80.4%). 1H NMR (400 MHz, CHLOROFORM-d)δ=4.11 (t, J=8.4 Hz, 2H), 3.92 (dd, J=6.5, 8.1 Hz, 2H), 3.51-3.17 (m,1H), 1.44 (s, 10H), 0.16 (s, 9H).

Step b) tert-Butyl 3-ethynylazetidine-1-carboxylate

To a solution of tert-butyl3-(2-trimethylsilylethynyl)azetidine-1-carboxylate (6243 mg, 24.64 mmol)in dry MeOH (40 mL) was added potassium carbonate (1700 mg, 12.32 mmol)at 25° C. and the reaction mixture was stirred at 25° C. for 2 h. Themixture was filtered, the filtrate was poured into saturated aq. NH4Clsolution (100 mL) and extracted with EA (100 mL three times). Thecombined organic layers were dried with anhydrous Na₂SO₄, filtered andthe filtrate concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel (PE:EA=50:1 to 15:1) toafford the title compound as light yellow oil (4100 mg, 91.8%). 1H NMR(400 MHz, CHLOROFORM-d) 6=4.16-4.11 (m, 2H), 3.93 (dd, J=6.5, 8.2 Hz,2H), 3.37-3.20 (m, 1H), 2.28 (d, J=2.4 Hz, 1H), 1.43 (s, 9H).

Step c) tert-Butyl3-[2-(2-fluoro-4-methyl-phenyl)ethynyl]azetidine-1-carboxylate

To a solution of tert-butyl 3-ethynylazetidine-1-carboxylate (1000.0 mg,5.52 mmol) and 4-bromo-3-fluorotoluene (1251.58 mg, 6.62 mmol, CAS RN452-74-4) in dry THF (20 mL) were added Pd(PPh3)4 (530.63 mg, 0.460mmol), CuI (87.83 mg, 0.460 mmol) and TEA (4644.2 mg, 46.0 mmol) at 25°C. The mixture was purged with N2 for 1 min and then stirred at 60° C.under N2 atmosphere for 12 h. The mixture was poured into saturated aq.NH4Cl solution (50 mL) and extracted three times with EtOAc (30 mLeach). The combined organic layers were dried with anhydrous Na₂SO₄,filtered, the filtrate was concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel (PE:EA=20:1to 10:1) to provide the desired compound as colorless oil (650 mg,40.7%). 1H NMR (400 MHz, CHLOROFORM-d) δ=7.33-7.28 (m, 1H), 6.94-6.85(m, 2H), 4.26-4.19 (m, 2H), 4.05 (dd, J=6.4, 8.1 Hz, 2H), 3.66-3.49 (m,1H), 2.36 (s, 3H), 1.46 (s, 9H).

Step d) tert-Butyl3-[2-(2-fluoro-4-methyl-phenyl)ethyl]azetidine-1-carboxylate

Batch a: To a solution of tert-butyl3-[2-(2-fluoro-4-methyl-phenyl)ethynyl]azetidine-1-carboxylate (50.0 mg,0.170 mmol, 1 eq) in EtOAc (5 mL) was added Pd/C (50.0 mg, wt.10%) at25° C. The mixture was stirred at 40° C. under a balloon of hydrogen gasfor 12 h. LCMS analysis found 79.8% of desired product.

Batch b: To a solution of tert-butyl3-[2-(2-fluoro-4-methyl-phenyl)ethynyl]azetidine-1-carboxylate (500.0mg, 1.73 mmol) in EtOAc (10 mL) was added Pd/C (250.0 mg, wt.10%) at 25°C. and the mixture was stirred at 40° C. under a balloon of hydrogen gasfor 6 h. LCMS found 80.4% of desired product. Batch a and b werecombined, the reaction mixture was filtered through a pad of celite, thefiltrate was concentrated under reduced pressure and the residue wasdried in vacuum to give the compound as colorless oil (350 mg, 69.0%).MS (ESI): m/z=238.1 [M−56+H]⁺.

BB164 3-[2-[4-Methoxy-2-(trifluoromethyl)phenyl]ethyl]azetidinetrifluoroacetate

To a solution of tert-butyl3-[2-(2-fluoro-4-methyl-phenyl)ethyl]azetidine-1-carboxylate (180.0 mg,0.5 mmol) in dry DCM (10 mL) was added TFA (1.0 mL, 1.19 mmol) at 25° C.and the mixture was stirred at 25° C. for 12 h. The reaction mixture wasconcentrated under reduced pressure and the residue was dried in vacuumto give the title compound (150 mg, 80.2%) as colorless oil. MS (ESI):m/z=260.1 [M+H]⁺.

Step a) tert-Butyl3-[2-[4-methoxy-2-(trifluoromethyl)phenyl]ethynyl]azetidine-1-carboxylate

To a solution of tert-butyl 3-ethynylazetidine-1-carboxylate (800.0 mg,4.41 mmol, BB111, intermediate b) and 3-trifluoromethyl-4-bromoanisole(1350.9 mg, 5.3 mmol, CAS RN 400-72-6) in dry THF (30 mL) at 25° C., wasadded Pd(PPh₃)₄ (509.41 mg, 0.440 mmol), CuI (84.31 mg, 0.440 mmol) andTEA (4458.42 mg, 44.14 mmol). The mixture was purged with N₂ for 1 minand then stirred at 60° C. under N₂ atmosphere for 12 h. The mixture waspoured into saturated aq. NH₄Cl solution (100 mL) and extracted threetimes with EtOAc (50 mL each). The organic layers were combined, driedwith anhydrous Na₂SO₄, filtered, the filtrate was concentrated withreduced pressure. The residue was purified by flash chromatography onsilica gel (PE:EA=20:1 to 10:1) to provide the product as colorless oil(160 mg, 8.2%). MS (ESI): m/z=300.1 [M−56+H]⁺.

Step b) tert-Butyl3-[2-[4-methoxy-2-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate

To a solution of tert-butyl3-[2-(2-fluoro-4-methyl-phenyl)ethynyl]azetidine-1-carboxylate (230.0mg, 0.65 mmol) in EtOAc (10 mL) at 25° C., was added Pd/C (150.0 mg,wt.10%), the mixture was stirred at 40° C. under a balloon of H₂ (about15 psi) for 12 h. The reaction mixture was filtered through a pad ofcelite and the filtrate was concentrated under reduced pressure. Theresidue was dried under vacuum to furnish the desired compound ascolorless oil (180 mg, 77.4%). MS (ESI): m/z=304.1 [M−56+H]⁺.

BB165 3-[[4-Methyl-2-(trifluoromethyl)phenyl]methoxy]azetidinetrifluoroacetate

To a solution of tert-butyl3-[[4-methyl-2-(trifluoromethyl)phenyl]methoxy]azetidine-1-carboxylate(130.0 mg, 0.380 mmol) in DCM (6.5 mL) was added TFA (1.3 mL, 16.87mmol) and the reaction was stirred at 20° C. After 12 h the mixture wasevaporated to give the desired crude product as light brown oil (130 mg,96.1%). MS (ESI): m/z=246.5 [M+H]⁺.

Step a) 4-Bromo-1-(Bromomethyl)-2-(trifluoromethyl)benzene

The solution of 5-bromo-2-methylbenzotrifluoride (2000 mg, 8.37 mmol,CAS RN 86845-27-4), N-bromosuccinimide (1489 mg, 8.37 mmol, CAS RN128-08-5) and benzoyl peroxide (101.34 mg, 0.420 mmol, CAS RN 2685-64-5)in carbon tetrachloride (30 mL) was stirred at 90° C. for 12 h. Themixture was evaporated and the residue was purified by silica gel columnchromatography (100% PE) to give the desired product as light brown oil(690 mg, 25.9%) which was used in the next step without furtherpurification.

Step b) tert-Butyl3-[[4-bromo-2-(Trifluoromethyl)phenyl]methoxy]azetidine-1-carboxylate

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (337.5 mg,1.95 mmol, CAS RN 22214-30-8) in THF (9 mL) was added t-BuOK (1.95 mL,1.95 mmol), then 4-bromo-1-(bromomethyl)-2-(trifluoromethyl) benzene(590.0 mg, 1.86 mmol) was added and the mixture was stirred at 20° C.for 12 h. The mixture was poured into aq. NH₄Cl solution (200 mL) andextracted three times with EtOAc (50 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated. The residuewas purified by prep-HPLC (ACN and water containing 0.225% v/v FA) togive the desired product as light brown oil (300 mg, 39.4%). MS (ESI):m/z=356.3 [M−56+H]⁺.

Step c) tert-Butyl3-[[4-Methyl-2-(trifluoromethyl)phenyl]methoxy]azetidine-1-carboxylate

To a solution of tert-butyl3-[[4-bromo-2-(trifluoromethyl)phenyl]methoxy]azetidine-1-carboxylate(250.0 mg, 0.610 mmol), trimethylboroxine (114.8 mg, 0.910 mmol), K₂CO₃(168.5 mg, 1.22 mmol) in 1,4-dioxane (10 mL) and H2O (2.5 mL) was addedPd(dppf)Cl₂ (89.18 mg, 0.120 mmol). The reaction was stirred at 100° C.for 12 h. The mixture was filtered, concentrated, and the residue waspurified by reversed flash chromatography (ACN and water containing 0.1%v/v FA) to give the desired product as light brown oil (146 mg, 69.4%).MS (ESI): m/z=290.4 [M−56+H]⁺.

BB166 3-[2-[2-Methoxy-6-(trifluoromethyl)phenyl]ethyl]azetidinetrifluoroacetate

To a solution of tert-butyl3-[2-[2-methoxy-6-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate(300.0 mg, 0.830 mmol) in DCM (5 mL), TFA (1.0 mL) was added and stirredat 25° C. for 1 h. The reaction mixture was evaporated under reducedpressure to give the desired product (300 mg, 96.3%) as colorless oil.MS (ESI): m/z=260.1 [M+H]⁺.

Step a) tert-Butyl3-[2-[2-methoxy-6-(trifluoromethyl)phenyl]ethynyl]azetidine-1-carboxylate

To a solution of tert-butyl 3-ethynylazetidine-1-carboxylate (710.6 mg,3.92 mmol, B111, intermediate b) and2-bromo-1-methoxy-3-(trifluoromethyl)benzene (500.0 mg, 1.96 mmol) indry DMSO (17.5 mL) at 25° C., was added Pd(PPh₃)₂Cl₂ (137.6 mg, 0.200mmol) and Cs₂CO₃ (1278 mg, 3.92 mmol). The mixture was purged with N₂for 1 min and then stirred at 110° C. under N₂ atmosphere for 12 h. Themixture was filtered, the filtrate was concentrated and the residue waspurified by silica gel (PE:EtOAc=20:1) to give the desired product aslight yellow oil (600 mg, 86.1%) that was used in the next step withoutfurther purification.

Step b) tert-Butyl 3-[2-[2-methoxy-6-(trifluoromethyl)phenyl]ethynyl]azetidine-1-carboxylate

To a solution of tert-butyl3-[2-[2-methoxy-6-(trifluoromethyl)phenyl]ethynyl]azetidine-1-carboxylate(400.0 mg, 1.13 mmol) in EtOAc (20 mL), wet Pd/C (50 mg, 10 wt. %) wasadded. The mixture was purged with H₂ 3 times and then stirred at 40° C.under H₂ atmosphere (balloon) for 12 h.

The mixture was filtered and the filtrate was concentrated to give thedesired product as light yellow oil (300 mg, 74.2% yield) which was usedin the next step without further purification.

BB167 3-[2-[4-Methyl-2-(trifluoromethyl)phenyl]ethyl]azetidinetrifluoroacetate

To a solution of tert-butyl3-[2-[4-methyl-2-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate(100.0 mg, 0.290 mmol) in DCM (4 mL) was added TFA (0.5 mL) and themixture was stirred at 20° C. for 12 h. The reaction mixture wasevaporated under reduced pressure to give the desired product as yellowoil (98 mg, 94.2%). MS (ESI): m/z=244.1 [M+H]⁺.

Step a) tert-Butyl3-[2-[4-methyl-2-(trifluoromethyl)phenyl]ethynyl]azetidine-1-carboxylate

To a solution of tert-butyl 3-ethynylazetidine-1-carboxylate (606.6 mg,3.35 mmol) and 2-bromo-5-methylbenzotrifluoride (400.0 mg, 1.67 mmol) indry DMSO (14.9 mL) at 25° C., was added Pd(PPh₃)₂Cl₂ (117.46 mg, 0.170mmol) and Cs₂CO₃ (1091 mg, 3.35 mmol). The mixture was purged with N₂for 1 min and then stirred at 110° C. under N₂ atmosphere for 12 h. Thereaction mixture was poured into H2O and extracted with EtOAc. Theorganic layer was evaporated and the residue was purified by silica gelcolumn chromatography (PE:EtOAc=20:1) to give the desired compound as ayellow oil (390 mg, 68.7% yield). MS (ESI): m/z=284.1 [M−56+H]⁺.

Step b) tert-Butyl3-[2-[4-methyl-2-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate

To a solution of tert-butyl3-[2-[4-methyl-2-(trifluoromethyl)phenyl]ethynyl]azetidine-1-carboxylate(390.0 mg, 1.15 mmol) in EtOAc (19.5 mL), wet Pd/C (150 mg, 10 wt. %)was added, the mixture was purged 3 times with H₂ and stirred at 40° C.under H₂ atmosphere (balloon) for 12 h. The mixture was filtered and thefiltrate was concentrated to give the desired product as light yellowoil (295 mg, 72.9% yield). MS (ESI): m/z=288.1 [M−56+H]⁺.

BB168 1-[2-[2-(Azetidin-3-yl)ethyl]-5-(trifluoromethyl)phenyl]ethanonetrifluoroacetate

To a solution of tert-butyl3-[2-[2-acetyl-4-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate(50.0 mg, 0.130 mmol) in DCM (1 mL) was added TFA (0.2 mL) and thesolution was stirred at 20° C. for 12 h. The mixture was concentrated togive the desired product as light brown oil (50 mg, 96.4% yield). MS(ESI): m/z=272.1 [M+H]⁺.

Step a) 2-Bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene

To a solution of [2-bromo-4-(trifluoromethyl)phenyl]methanol (500.0 mg,1.96 mmol, CAS RN 497959-33-8) and PPh3 (770.5 mg, 2.94 mmol) in THF (10mL) was added carbon tetrabromide (975.3 mg, 2.94 mmol), and the mixturewas stirred at 25° C. for 12 h. The reaction was concentrated in vacuumand the residue was purified by silica gel column chromatography(PE:EA=0:1˜20:1) to yield the desired product as colorless oil (600 mg,96.3% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.78 (s, 1H), 7.55-7.46(m, 2H), 4.53 (s, 2H).

Step b) 2-Bromo-1-(diethoxyphosphorylmethyl)-4-(trifluoromethyl)benzene

A solution of 2-bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene (600.0mg, 1.89 mmol) in triethyl phosphite (3136 mg, 18.87 mmol) was stirredat 160° C. for 5 h. The mixture was concentrated at 100° C. underreduced pressure to remove most of the triethyl phosphite to give thecrude product (700 mg) as light yellow oil. MS (ESI): m/z=375.2 [M+H]⁺.

Step c) tert-Butyl3-[(E)-2-[2-bromo-4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate

A mixture of2-bromo-1-(diethoxyphosphorylmethyl)-4-(trifluoromethyl)benzene (600.0mg, 1.6 mmol) in THF (10 mL) was added to another suspension of NaH(191.9 mg, 4.8 mmol, 60% dispersion in mineral oil) in THF (10 mL) at 0°C. The mixture was stirred at 0° C. for 1 h. Then tert-butyl3-formylazetidine-1-carboxylate (296.3 mg, 1.6 mmol) was added and themixture was stirred at 20° C. for 11 h. The reaction mixture was pouredinto aq. NH₄Cl solution (100 mL) and extracted three times with EtOAc(50 mL each). The combined organic layers were washed with brine (100mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by silica gel column chromatography (PE:EtOAc=20:1) to give thedesired product as light yellow oil (450 mg, 69.3%). MS (ESI): m/z=352.0[M56+H]⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.74 (d, J=0.8 Hz, 1H),7.58-7.51 (m, 1H), 7.49-7.41 (m, 1H), 6.71 (d, J=15.8 Hz, 1H), 6.36 (dd,J=8.4, 15.8 Hz, 1H), 4.13 (t, J=8.5 Hz, 2H), 3.78 (dd, J=5.8, 8.6 Hz,2H), 3.44-3.31 (m, 1H), 1.39 (s, 9H).

Step d) tert-Butyl3-[(E)-2-[2-acetyl-4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate

A solution of tributyl(1-ethoxyvinyl)tin (426.7 mg, 1.18 mmol),tert-butyl3-[(E)-2-[2-bromo-4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate(400.0 mg, 0.980 mmol) and Pd(Ph₃P)₂Cl₂ (138.2 mg, 0.200 mmol) in THF(16 mL) was stirred at 80° C. under N₂ atmosphere for 4 h. The mixturewas cooled down to room temperature and aq. KF solution (10 mL) wasadded. The mixture was stirred for 10 mins, extracted three times withEtOAc (20 mL each) and the combined organic layers were concentrated.The residue was dissolved in THF (20 mL) and aq. HCl (0.6 N, 20 mL) wasadded. The mixture was stirred at 20° C. for 0.5 h, extracted threetimes with EtOAc (20 mL each) and the combined organic layers wereconcentrated. The residue was purified by silica gel columnchromatography (PE:EtOAc=20:1) to give the desired product (280 mg, 77%yield) as light yellow oil. MS (ESI): m/z=314.1 [M−56+H]⁺.

Step e) tert-Butyl3-[2-[2-acetyl-4-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate

To a solution of tert-butyl3-[(E)-2-[2-acetyl-4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate(50.0 mg, 0.140 mmol) in EtOAc (5 mL) was added wet Pd/C (20.0 mg, 10wt. %) and the mixture was stirred at 20° C. under H₂ (balloon)atmosphere for 12 h. The reaction was then warmed up to 50° C. andstirred for another 12 h. The mixture was filtered and the filtrate wasconcentrated to give the desired product (50 mg, 99.5%) as light yellowoil. MS (ESI): m/z=316.2 [M−56+H]⁺.

BB169 3-[2-[2-Bromo-4-(trifluoromethyl)phenyl]ethyl]azetidinetrifluoroacetate

To a solution of tert-butyl3-[2-[2-bromo-4-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate(400.0 mg, 0.980 mmol) in DCM (10 mL) was added TFA (1.0 mL) and themixture was stirred at 20° C. for 12 h. The reaction mixture wasevaporated under reduced pressure to give the desired product (413 mg,99.8% yield) as yellow oil. MS (ESI): m/z=308.1 [M+H]⁺.

Step a) tert-Butyl3-[2-[2-bromo-4-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate

To a suspension of tert-butyl 3-[(E)-2-[2-bromo-4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate (600.0 mg, 1.48 mmol, BB116,intermediate c) and MgO (118.1 mg, 2.95 mmol) in EtOAc (20 mL) was addedPd/C (300.0 mg, 10 wt. %), the mixture was stirred at 25° C. under H₂atmosphere (balloon) for 1 h. The reaction mixture was filtered and thefiltrate was evaporated under reduced pressure to give the desiredproduct (500 mg, 82.9%) as light yellow oil. MS (ESI): m/z=352.0[M-56+H]⁺.

BB174 2-(Azetidin-3-ylmethoxy)-5-(trifluoromethyl)pyridine2,2,2-trifluoroacetate

Synthesis of BB174 was performed in analogy to BB57, starting fromtert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate and2-bromo-5-(trifluoromethyl)pyridine. MS (ESI): m/z=233.1 [M+H]⁺.

BB1753-Methyl-5-[[rac-(3R,4R)-3-methyl-4-piperidyl]methoxy]-2-(trifluoromethyl)pyridinedihydrochloride

tert-Butyl(rac-3R,4R)-3-methyl-4-(((5-methyl-6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate(198 mg, 510 μmol) was dissolved in DCM (2 mL) and HCl 2M in ether (1.53mL, 3.06 mmol) was added. The reaction mixture was stirred at RT for 8h. The reaction mixture was concentrated in vacuo to yield 180 mg ofdesired product as white solid (98%) MS (ESI): m/z=289.3 [M+H]⁺.

a) tert-Butyl(rac-3R,4R)-4-(hydroxymethyl)-3-methylpiperidine-1-carboxylate

To a stirred solution of cis-N—BOC-3-methylpiperidine-4-carboxylic acidmethyl ester (2 g, 7.77 mmol) in THF (10 ml) was added lithiumborohydride (5.83 mL, 11.7 mmol) at 2-5° C. The reaction mixture wasthen heated at reflux for 3 h and then cooled to 2-5° C. Water was addedand the aqueous layer was extracted twice with EtOAc (30 mL each). Theorganic layer was washed with water, NaHCO₃and brine, the layers wereseparated, and the organics dried over Na₂SO₄ and concentrated invacuum. Purification by flash chromatography (gradient of EtOAc inn-heptane, 0 to 65%) provided the product as a colorless oil (930 mg,50%). MS (ESI): m/z=174.1 [M−56+H]⁺.

b) tert-Butyl(rac-3R,4R)-3-methyl-4-(((5-methyl-6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate

tert-butyl (3R,4R)-4-(hydroxymethyl)-3-methylpiperidine-1-carboxylate(239 mg, 1.04 mmol) was dissolved in DMF (4.17 mL) and NaH in mineraloil (60%, 45.8 mg, 1.15 mmol) was added at RT. The reaction was stirredfor 20 min, then 5-bromo-3-methyl-2-(trifluoromethyl)pyridine (250 mg,167 μL, 1.04 mmol) was added and stirring continued for 12 h at RT. Thereaction was quenched with 10 mL sat. NH₄Cl solution and extracted threetimes with water/EtOAc. The organic phases were combined and dried overMgSO₄ and the solvent was removed in vacuo. Flash chromatography(gradient of EtOAc in n-heptane, 0 to 50%) yielded the product as whitesolid (148 mg, 49%). MS (ESI): m/z=333.2 [M−56+H]⁺.

BB176 3-((2-Fluoro-4-(trifluoromethyl)benzyl)oxy)-2-methylazetidine2,2,2-trifluoroacetate

To a solution of tert-butyl3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)-2-methylazetidine-1-carboxylate(0.265 g, 729 μmol) in DCM (4 mL) was added TFA (832 mg, 562 μL, 7.29mmol). The resultant reaction mixture was stirred at RT for 1 h. Thereaction mixture was concentrated to give the title compound as acolorless oil. The crude product was used without further purification.MS (ESI): m/z=264.2 [M+H]⁺.

Step a) [2-Fluoro-4-(trifluoromethyl)phenyl]methyl methanesulfonate

To an ice-cold solution of (2-fluoro-4-(trifluoromethyl)phenyl)methanol(840 mg, 4.33 mmol) and triethylamine (1.31 g, 1.81 mL, 13 mmol) in DCM(8 mL) was added dropwise methanesulfonyl chloride (496 mg, 337 μL, 4.33mmol) and the mixture was stirred at 0° C. for 1 h. The reaction mixturewas poured on saturated aqueous NaHCO₃ solution (10 mL) and DCM (20 mL)and the layers were separated. The aqueous layer was extracted once withDCM (20 mL). The organic layers were washed once with brine, dried overMgSO₄, filtered and evaporated to yield the desired compound as a yellowoil (1.13 g, 96%).

Step b) tert-Butyl3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]-2-methyl-azetidine-1-carboxylate

To an ice-cold solution of tert-butyl3-hydroxy-2-methylazetidine-1-carboxylate (250 mg, 1.34 mmol) in DMF (3mL) was added NaH (60% in mineral oil, 58.7 mg, 1.47 mmol) in portionsand the mixture was stirred at ice-bath temperature for 5 min followedby stirring at RT for 40 min. A solution of2-fluoro-4-(trifluoromethyl)benzyl methanesulfonate (436 mg, 1.6 mmol)in DMF (1 mL) was added dropwise to the mixture at RT. Stirring of theslurry was continued at RT for 16 h. The reaction mixture was poured onsaturated aqueous NH₄Cl solution (10 mL) and EtOAc (20 mL) and thelayers were separated. The aqueous layer was extracted once with EtOAc(50 mL). The organic layers were washed twice with water, dried overNa₂SO₄, filtered, and concentrated. The crude compound was purified bysilica gel chromatography (gradient of n-heptane:EtOAc 100:0 to 0:100)to get tert-butyl3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]-2-methyl-azetidine-1-carboxylateas a colorless oil (0.265 g, 54.6% yield). MS (ESI): m/z=308.2[M−56+H]⁺.

BB 177 2-(Azetidin-3-ylmethoxy)-4,5-bis(trifluoromethyl)pyridine2,2,2-trifluoroacetate

Synthesis of BB177 was performed in analogy to BB57, starting fromtert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate and2-chloro-4,5-bis(trifluoromethyl)pyridine. MS (ESI): m/z=301.2 [M+H]⁺.

BB179 3-((4-Chloro-2-phenoxybenzyl)oxy)azetidine 2,2,2-trifluoroacetate

Synthesis of BB179 was done in analogy to BB39, starting from tert-butyl3-hydroxyazetidine-1-carboxylate and1-(bromomethyl)-4-chloro-2-phenoxybenzene (synthesis described below).MS (ESI): m/z=290.2 [M+H]⁺.

1-(Bromomethyl)-4-chloro-2-phenoxybenzene

i) In a 10 mL round-bottomed flask, methyl 4-chloro-2-phenoxybenzoate(547 mg, 2.08 mmol) was diluted in toluene (3.82 mL) and the reactionmixture was cooled in an ice bath. Sodium bis(2-methoxyethoxy)aluminumhydride 70% in toluene (649 mg, 637 μL, 2.25 mmol) was added dropwiseslowly at max. 15° C. to give a light yellow solution. The reactionmixture was stirred at r.t. for 30 min. The crude reaction mixture,containing the product (4-chloro-2-phenoxyphenyl)methanol was useddirectly in the next step.

ii) In a 25 mL round-bottomed flask, hydrobromic acid 48% in H₂O (6.49g, 4.35 mL, 38.5 mmol) was cooled in an ice bath. Then4-chloro-2-phenoxyphenyl)methanol (crude, 488 mg, 2.08 mmol) was addeddropwise slowly and the mixture was stirred at 50° C. for 2 h.Hydrobromic acid 48% in H₂O (6.25 g, 2.18 mL, 19.25 mmol) was added andthe mixture was stirred at 60° C. for 1 h, then cooled to RT. Theaqueous phase was separated, the organic phase was washed four timeswith H₂O and evaporated. The crude material was purified by flash columnchromatography (gradient 0% to 25% EtOAc in hexanes) and was used in thenext step without further purification. Yield: 85%.

BB 181 3-((1-(2,4-Dichlorophenyl)cyclopropyl)methoxy)azetidine2,2,2-trifluoroacetate

To a solution of tert-Butyl3-((1-(2,4-dichlorophenyl)cyclopropyl)methoxy)azetidine-1-carboxylate(165 mg, 443 μmol) in DCM (2 mL) was added TFA (202 mg, 137 μL, 1.77mmol) and the reaction stirred at RT for 8 h. The mixture wasconcentrated in vacuo (azeotrop with toluene, EtOAc and n-heptane) toprovide the compound as a colorless oil (170 mg, 99%). MS (ESI):m/z=272.2 [M+H]⁺.

Step a) l-(2,4-Dichlorophenyl)cyclopropyl)methanol

In a 50 mL three-necked flask,1-(2,4-dichlorophenyl)cyclopropane-1-carboxylic acid (1 g, 4.33 mmol)was combined with THF (20 mL) to give a colorless solution. At 0° C.,borane tetrahydrofuran complex solution 1.0 M in THF (6.49 mL, 6.49mmol) was added dropwise over a period of 15 min. The reaction wasstirred at RT for 2 h. MeOH (2 mL) was added dropwise followed by 1M aq.HCl solution and stirred for 30 min. The reaction mixture was extractedtwice with EtOAc (40 mL each) and the organic layers were washed with10% aq Na₂CO₃ solution (40 mL) followed by brine (40 mL). The organicfractions were combined and dried over Na₂SO₄ and concentrated in vacuo.The crude material was purified by flash column chromatography (gradientEtOAc in n-heptane, 0% to 30%) to yield the compound as colorless oil(90%) MS (ESI): m/z=201.0 [M−16+H]⁺.

Step b) 1-(2,4-Dichlorophenyl)cyclopropyl]methyl methanesulfonate

To an ice-cold solution of (1-(2,4-dichlorophenyl)cyclopropyl)methanol(350 mg, 1.61 mmol) and TEA (326 mg, 449 μL, 3.22 mmol) in DCM (6 mL)was added dropwise methanesulfonyl chloride (185 mg, 126 μL, 1.61 mmol)and the mixture was stirred at 0° C. for 1 h, then at RT overnight. Thereaction mixture was poured on saturated aqueous NaHCO₃ solution (10 mL)and DCM (10 mL) and the layers were separated. The aqueous layer wasextracted once with DCM (10 mL). The organic layers were washed withbrine, dried over MgSO₄, filtered and evaporated to furnish the desiredintermediate mesylate compound as a yellow oil (435 mg, 91%). MS (ESI):m/z=201.0 [M-mesyl+H]⁺.

Step c) tert-Butyl3-((1-(2,4-dichlorophenyl)cyclopropyl)methoxy)azetidine-1-carboxylate

To an ice-cold solution of tert-butyl 3-hydroxyazetidine-1-carboxylate(220 mg, 1.27 mmol) in DMF (4 mL) was added sodium hydride in mineraloil (60%, 61 mg, 1.52 mmol) in portions and the mixture was stirred atice-bath temperature for 5 min followed by stirring at RT for 40 min. Asolution of 1-(2,4-dichlorophenyl)cyclopropyl)methyl methanesulfonate(431 mg, 1.46 mmol) was dissolved in DMF (1 mL) and added dropwise tothe mixture at RT. Stirring of the slurry was continued at RT for 16 h,then at 55° C. for 2.5 h. The reaction mixture was poured on saturatedaqueous NH₄Cl solution (10 mL) and EtOAc (20 mL) and the layers wereseparated. The aqueous layer was extracted once with EtOAc (50 mL). Theorganic layers were washed twice with water, dried over MgSO₄, filteredand evaporated. Flash Chromatography (gradient of EtOAc in n-heptane 0to 40%) yielded the product as colorless oil (165 mg, 35%) MS (ESI):m/z=316.2 [M−56+H]⁺.

BB1822-((Azetidin-3-yloxy)methyl)-6-(4-fluorophenoxy)-4-(trifluoromethyl)pyridine4-methylbenzenesulfonate

Tert-butyl3-((6-(4-fluorophenoxy)-4-(trifluoromethyl)pyridin-2-yl)methoxy)azetidine-1-carboxylate(150 mg, 339 μmol) was dissolved under argon in EtOAc (2 mL),p-toluenesulfonic acid monohydrate (77.4 mg, 407 μmol) was added and themixture was stirred at RT for 5 min, then for 80° C. 3 h at and at RTover night. The reaction mixture was evaporated to provide the compoundas 180 mg of a yellow oil which was used in the next step withoutfurther purification. MS (ESI): m/z=343.2 [M+H]⁺.

Step a) tert-Butyl3-((6-bromo-4-(trifluoromethyl)pyridin-2-yl)methoxy)azetidine-1-carboxylate

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (272 mg,1.57 mmol) in dry THF (8 mL) was added potassium tert-butoxide 1M in THF(1.57 mL, 1.57 mmol) and the turbid reaction mixture was stirred at RTfor 30 min. 2-Bromo-6-(bromomethyl)-4-(trifluoromethyl)pyridine (500 mg,1.57 mmol) was added at 0-2° C. and the reaction stirred at 0-2° C. for20 min. The reaction mixture was then stirred at RT for 16 h. Thereaction mixture was diluted with EtOAc, extracted with water, theorganic phase was collected and the aqueous phase was back-extractedwith EtOAc. The combined organic layers were dried over sodium sulfateand evaporated down to dryness. The crude material was purified by flashcolumn chromatography (gradient of EtOAc in n-heptane, 0% to 40%) toprovide the product as light yellow oil (41%) MS (ESI): m/z=355.1[M−56+H]⁺.

Step b) tert-Butyl3-[[6-(4-fluorophenoxy)-4-(trifluoromethyl)-2-pyridyl]methoxy]azetidine-1-carboxylate

tert-Butyl3-((6-bromo-4-(trifluoromethyl)pyridin-2-yl)methoxy)azetidine-1-carboxylate(260 mg, 632 μmol) and 4-fluorophenol (70.9 mg, 632 μmol) were dissolvedin DMF (2 mL), then K₂CO₃ (131 mg, 948 μmol) was added and the mixturewas stirred at 80° for 30 h. The reaction mixture was evaporated undervacuum and the residue was dissolved in EtOAc and extracted with waterand brine. The organic layers were dried over MgSO₄, filtered and thesolvent was removed under vacuum. The residue was purified by flashchromatography (gradient of EtOAc in n-heptane, 0 to 30%) to yield theproduct as a light yellow oil (93%). MS (ESI): m/z=443.4 [M+H]⁺.

BB1836-((Azetidin-3-yloxy)methyl)-2-(4-fluorophenoxy)-3-(trifluoromethyl)pyridine4-methylbenzenesulfonate

tert-Butyl3-((6-(4-fluorophenoxy)-5-(trifluoromethyl)pyridin-2-yl)methoxy)azetidine-1-carboxylate(170 mg, 384 μmol) was dissolved under argon atmosphere in EtOAc (2.27mL) and p-toluenesulfonic acid monohydrate (87.7 mg, 461 μmol) wasadded. The reaction was stirred at RT for 5 min, then at 80° C. for 3 hand stirred at RT over night. The reaction mixture was evaporated underreduced pressure to dryness to provide the desired product as lightyellow oil (89%) MS (ESI): m/z=343.2 [M+H]⁺.

Step a) Methyl 6-(4-fluorophenoxy)-5-(trifluoromethyl)picolinate

Methyl 6-chloro-5-(trifluoromethyl)picolinate (800 mg, 3.34 mmol),4-fluorophenol (412 mg, 3.67 mmol) and K₂CO₃ (692 mg, 5.01 mmol) weredissolved in DMF (6 mL) and stirred at 80° C. for 6 h. The reactionmixture was cooled to RT and extracted three times with water (20 mLeach), twice with EtOAc (30 mL each), brine (20 mL), dried over MgSO₄,filtered and evaporated in vacuo. The crude residue was purified byflash column chromatography (gradient of EtOAc in n-heptane, 0 to 50%)to provide the product as white solid (67%). MS (ESI): m/z=316.1 [M+H]⁺.

Step b) (6-(4-Fluorophenoxy)-5-(trifluoromethyl)pyridin-2-yl)methanol

To a stirred solution of methyl6-(4-fluorophenoxy)-5-(trifluoromethyl)picolinate (705 mg, 2.24 mmol) inTHF (8 mL) was added lithium borohydride 2M in THF (1.34 mL, 2.68 mmol)at 2-5° C. The reaction mixture was stirred at RT for 3 h and thencooled to 2-4° C. and quenched with 10 mL water (slowly added). Theaqueous layer was extracted twice with EtOAc (30 mL each) and thecombined organic layers were washed with water, 10 mL NaHCO₃ solutionand 10 mL brine. The organic layer was dried over Na₂SO₄ andconcentrated in vacuum. Purification by flash column chromatography(gradient of EtOAc in n-heptane, 0 to 50%) yielded the product as acolorless solid (95%). MS (ESI): m/z=288.2 [M+H]⁺.

Step c) 6-(Bromomethyl)-2-(4-fluorophenoxy)-3-(trifluoromethyl)pyridine

To a solution of(6-(4-fluorophenoxy)-5-(trifluoromethyl)pyridin-2-yl)methanol (330 mg,1.15 mmol) in dry DCM (5 mL) was added tetrabromomethane (457 mg, 1.38mmol). The mixture was cooled to 0-3° C. and over 10 mintriphenylphosphine (392 mg, 1.49 mmol) in 1 mL dry DCM was added. Themixture was stirred 1 hr at 2-4° C., then 20 mL DCM and silica gel wasadded. The solvent was removed in vacuo and the residue subjected tocolumn flash chromatography (gradient of EtOAC in n-heptane, 0 to 40%)to yield the desired product as a colorless oil (94%). MS (ESI):m/z=350.0 [M+H]⁺.

Step d) tert-Butyl3-((6-(4-fluorophenoxy)-5-(trifluoromethyl)pyridin-2-yl)methoxy)azetidine-1-carboxylate

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (183 mg,1.06 mmol) in dry THF (5 mL) was added potassium tert-butoxide 1M in THF(1.11 mL, 1.11 mmol) and the reaction mixture was stirred at RT for 15min. Then,6-(bromomethyl)-2-(4-fluorophenoxy)-3-(trifluoromethyl)pyridine (370 mg,1.06 mmol) was added. The reaction mixture was stirred at RT for 1 h andthen diluted with EtOAc and extracted with 1M aq. NaHCO₃solution. Theorganic phase was collected and the aqueous phase was back-extractedwith EtOAc. The combined organic phases were dried over sodium sulfateand evaporated down to dryness. The residue was purified by column flashchromatography (gradient of EtOAc in n-heptane, 0 to 30%) to furnish theproduct as a colorless oil (34%). MS (ESI): m/z=387.2 [M−56+H]⁺.

BB184 2-((Azetidin-3-yloxy)methyl)-4-(4-fluorophenyl)thiazole2,2,2-trifluoroacetate

To a solution of tert-butyl3-((4-(4-fluorophenyl)thiazol-2-yl)methoxy)azetidine-1-carboxylate (150mg, 412 μmol) in dry DCM (1.5 mL) under argon atmosphere was added TFA(282 mg, 190 μL, 2.47 mmol) and the solution was stirred at RT for 8 h.The reaction mixture was concentrated in vacuo (azeotrop with toluene,EtOAc and heptane) to yield the desired product as a yellow solid (98%).MS (ESI): m/z=265.2 [M+H]⁺.

Step a) (4-(4-Fluorophenyl)thiazol-2-yl)methanol

To a stirred solution of ethyl 4-(4-fluorophenyl)thiazole-2-carboxylate(835 mg, 3.32 mmol) in dry THF (10 mL) was added lithium borohydride 2Min THF (1.99 mL, 3.99 mmol) at 2-5° C. The reaction mixture was stirredat RT for 3 h, then cooled to 2-4° C. and quenched with water (10 mLslowly added). The aqueous layer was extracted twice with EtOAc (30 mLeach) and the organic layers were washed with water, 10 mL NaHCO₃solution and 10 mL brine. The combined organic layers were dried overNa₂SO₄ and concentrated in vacuum. The residue was purified by columnflash chromatography (gradient of EtOAc in n-heptane, 0 to 60%) to yieldthe desired product as a white solid (94%) MS (ESI): m/z=210.1 [M+H]⁺.

Step b) 2-(Bromomethyl)-4-(4-fluorophenyl)thiazole

To a solution of (4-(4-fluorophenyl)thiazol-2-yl)methanol (400 mg, 1.91mmol) in dry DCM (7 mL) was added tetrabromomethane (761 mg, 2.29 mmol),the solution was cooled to 0-3° C. and triphenylphosphine (652 mg, 2.49mmol) in 1 mL dry DCM was added over 10 min. The mixture was stirred at2-4° C. for 1 h, then 20 mL DCM were added. The reaction mixture wasextracted with water, saturated NH₄Cl solution and brine. The organicphase was dried over MgSO₄, filtered and evaporated. The residue waspurified by flash chromatography (gradient of EtOAc in n-heptane, 0 to40%) to provide 480 mg of the title compound as a light yellow oil(83%). MS (ESI): m/z=273.9 [M+H]⁺.

Step c) tert-Butyl3-((4-(4-fluorophenyl)thiazol-2-yl)methoxy)azetidine-1-carboxylate

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (293 mg,1.69 mmol) in dry THF (6 mL) was added potassium tert-butoxide 1M in THF(1.77 mL, 1.77 mmol) and the reaction mixture was stirred at RT for 15min. After cooling down to 2-4° C.2-(bromomethyl)-4-(4-fluorophenyl)thiazole (460 mg, 1.69 mmol) in 1 mLTHF was added. The reaction mixture was stirred at RT for 1 h, dilutedwith EtOAc and extracted with 1M aq. NaHCO₃ solution. The organic phasewas collected and the aqueous phase was back-extracted with EtOAc. Thecombined organic phases were dried over Na₂SO₄ and evaporated down todryness. The residue was purified by column flash chromatography(gradient of EtOAc in n-heptane, 0 to 40%) to furnish the desiredproduct as a light yellow solid (89%). MS (ESI): m/z=365.2 [M+H]⁺.

BB186rac-(2R,3S)-3-(2-Bromo-5-(trifluoromethyl)phenoxy)-2-methylpyrrolidine2,2,2-trifluoroacetate

To a solution of rac-tert-butyl(2R,3S)-3-(2-bromo-5-(trifluoromethyl)phenoxy)-2-methylpyrrolidine-1-carboxylate(225 mg, 530 μmol) in dry DCM (2 mL) under argon atmosphere was addedTFA (242 mg, 163 μL, 2.12 mmol) and the solution was stirred at RT overnight. The reaction mixture was concentrated in vacuo to dryness(azeotrop with n-heptane) to provide 233 mg of the title compound as acolorless oil (97%). MS (ESI): m/z=324.1 [M+H]⁺.

Step a) rac-tert-Butyl(2R,3S)-3-(2-bromo-5-(trifluoromethyl)phenoxy)-2-methylpyrrolidine-1-carboxylate

To a solution of rac-tert-butyl(2R,3S)-3-hydroxy-2-methylpyrrolidine-1-carboxylate (CAS: 1807941-04-3,150 mg, 745 μmol) in dry THF (4 mL) under argon atmosphere was addedpotassium tert-butoxide 1M in THF (783 μL, 783 μmol). The mixture wasstirred at RT for 15 min, then cooled down to 2-4° C. and a solution of1-bromo-2-fluoro-4-(trifluoromethyl)benzene (181 mg, 745 μmol) in 0.5 mLdry THF was added slowly. The mixture was stirred at RT for 2 h and thenextracted with EtOAc and aqueous 5% NaHCO₃solution followed by water andbrine.

The organic phase was dried over MgSO₄, filtered off and evaporated todryness. The residue was purified by column flash chromatography(gradient of EtOAc in n-heptane, 0 to 40%) to yield the product as lightyellow oil (71%). MS (ESI): m/z=368 [M−56+H]⁺.

The following intermediates were synthesized from 4-nitrophenyl(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate(BB7a) and the suitable building blocks in analogy to the reactionmethods described herein.

BB No. Building block(s) MS, m/z Method BB203 BB198 480.1 A10 withoutDMAP [M + H]⁺ BB204 BB201 445.1 A10 without DMAP [M + H]⁺

BB2063-[2-[2-Fluoro-4-(trifluoromethyl)phenyl]ethyl]azetidine;4-methylbenzenesulfonicacid

The compound was prepared in analogy to BB95 from tert-butyl3-(2-fluoro-4-(trifluoromethyl)phenethyl)azetidine-1-carboxylate and4-methylbenzenesulfonic acid monohydrate. Upon cooling a suspensionformed which was filtered. The filter cake was washed with a smallvolume of EtOAc to provide the desired product as a colorless solid(71.6%). MS (ESI): m/z=248.2 [M+H]⁺.

Step a) Diethyl (2-fluoro-4-(trifluoromethyl)benzyl)phosphonate

The compound was prepared in analogy to BB159, step a, from1-(bromomethyl)-2-fluoro-4-(trifluoromethyl)benzene and triethylphosphite. Colorless oil (83.4%). MS (ESI): m/z=315.2 [M+H]⁺.

Step b) tert-Butyl3-[(E)-2-[2-fluoro-4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate

The compound was prepared in analogy to BB95, step a, from diethyl(2-fluoro-4-(trifluoromethyl)benzyl)phosphonate and tert-butyl3-formylazetidine-1-carboxylate to yield the compound as a colorless oil(69.9%). MS (ESI): m/z=290.1 [M−56+H]⁺.

Step c) tert-Butyl3-[2-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate

The compound was prepared in analogy to BB95, step b, from tert-butyl3-[(E)-2-[2-fluoro-4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate.Colorless oil (92.0%). MS (ESI): m/z=292.2 [M−56+H]⁺.

BB208 3-[2,2-Difluoro-2-[4-(trifluoromethyl)phenyl]ethyl]azetidine;4-methylbenzenesulfonic acid

The compound was prepared in analogy to BB95 from tert-butyl3-(2,2-difluoro-2-(4-(trifluoromethyl)phenyl)ethyl)azetidine-1-carboxylateand 4-methylbenzenesulfonic acid monohydrate and using the materialisolated from the filtrate after evaporation, which was used withoutfurther purification (30%). MS (ESI): m/z=266.2 [M+H]⁺.

Step a) tert-Butyl3-[2-[methoxy(methyl)amino]-2-oxo-ethyl]azetidine-1-carboxylate

To a suspension of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid(2 g, 9.29 mmol) and HATU (3.89 g, 10.2 mmol) in DCM (65 mL) was addedDIPEA (2.64 g, 3.57 mL, 20.4 mmol) and the mixture was stirred at RT for30 min before N,O-dimethylhydroxylamine hydrochloride (906 mg, 9.29mmol) was added. Stirring was continued at RT overnight. The reactionmixture was poured on saturated aqueous NH₄Cl solution and EtOAc and thelayers were separated. The aqueous layer was extracted twice with EtOAc.The organic layers were washed twice with water, dried over MgSO₄,filtered, treated with silica gel and evaporated. The compound waspurified by silica gel chromatography on a 25 g column using an MPLCsystem eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100) tofurnish the desired compound as a colorless oil (100%) which was used inthe next step without further purification. MS (ESI): m/z=203.2[M−56+H]⁺.

Step b) tert-Butyl3-[2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate

To an ice-cold solution of tert-butyl3-(2-(methoxy(methyl)amino)-2-oxoethyl)azetidine-1-carboxylate (0.8 g,3.1 mmol) in THF (5 mL) in an argon-flushed and heat-dried 2-neck flaskwas added dropwise a turbid solution of(4-(trifluoromethyl)phenyl)magnesium bromide 2.22 M in THF (1.95 mL,4.34 mmol). The brown solution was stirred in an ice-bath for 2.5 hallowing the temperature to rise to RT. The reaction mixture was pouredon saturated aqueous NH₄Cl solution and EtOAc and the layers wereseparated. The aqueous layer was extracted twice with EtOAc. The organiclayers were dried over MgSO₄, filtered, treated with silica gel andevaporated. The compound was purified by silica gel chromatography on a25 g column using an MPLC system eluting with a gradient ofn-heptane:EtOAc (100:0 to 0:100) to provide the desired compound as acolorless solid (25.9%). MS (ESI): m/z=342.3 [M−H]³¹.

Step c) tert-Butyl3-[2,2-difluoro-2-[4-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate

To a solution of tert-butyl3-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)azetidine-1-carboxylate (50mg, 146 μmol) in toluene (0.3 mL) under argon was addedbis(2-methoxyethyl)aminosulphur trifluoride (50% solution in THF, 387mg, 379 μL, 874 μmol) and the mixture was stirred at 80° C. for 19 h.The dark mixture was allowed to cool down and another batch ofbis(2-methoxyethyl)aminosulphur trifluoride (50% solution in THF, 387mg, 379 μL, 874 μmol) was added. Heating was continued at 80° C. foranother 4 h. The reaction mixture was poured on saturated aqueous NaHCO₃solution and EtOAc and the layers were separated. The aqueous layer wasextracted twice with EtOAc. The organic layers were dried over MgSO₄,filtered, treated with silica gel and evaporated. The compound waspurified by silica gel chromatography on a 4 g column using an MPLCsystem eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50) toyield the desired compound as a light brown oil (45.1%). MS (ESI):m/z=266.1 [M+H]⁺.

BB2093-[2-Fluoro-5-(trifluoromethyl)phenoxy]pyrrolidine;4-methylbenzenesulfonicacid

The compound was prepared in analogy to BB95 from tert-butyl3-[2-fluoro-5-(trifluoromethyl)phenoxy]pyrrolidine-1-carboxylate.Colorless oil which was used in the next step without furtherpurification. MS (ESI): m/z=250.1 [M+H]⁺.

Step a) tert-Butyl3-[2-fluoro-5-(trifluoromethyl)phenoxy]pyrrolidine-1-carboxylate

To a solution of 2-fluoro-5-(trifluoromethyl)phenol (321 mg, 1.78 mmol),tert-butyl 3-hydroxypyrrolidine-1-carboxylate (334 mg, 1.78 mmol; CASRN: 103057-44-9) and triphenylphosphine (467 mg, 1.78 mmol) in THF (5mL) was added (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (450 mg,1.78 mmol, CAS RN 10465-81-3) in portions and the mixture was stirred atRT for 40 h. Silica gel was added to the suspension and it wasevaporated. The compound was purified by silica gel chromatography on a24 g column using an MPLC (ISCO) system eluting with a gradient ofn-heptane:EtOAc (100:0 to 75:25) to provide the desired compound as acolorless oil (8.3%) which was used in the next step without furtherpurification. MS (ESI): m/z=294.1 [M−56+H]⁺.

BB2103-[2-Chloro-5-(trifluoromethyl)phenoxy]pyrrolidine;4-methylbenzenesulfonicacid

The compound was prepared in analogy to BB95 from tert-butyl3-[2-chloro-5-(trifluoromethyl)phenoxy]pyrrolidine-1-carboxylate.Colorless oil. MS (ESI): m/z=266.1 [M+H]⁺.

Step a) tert-Butyl3-[2-chloro-5-(trifluoromethyl)phenoxy]pyrrolidine-1-carboxylate

The compound was prepared in analogy to BB209, step a, from2-chloro-5-(trifluoromethyl)phenol and tert-butyl3-hydroxypyrrolidine-1-carboxylate. Colorless solid which was used afterchromatography without further purification. MS (ESI): m/z=310.1[M−56+H]⁺.

BB2113-[(E)-2-(2-fluoro-4-methyl-phenyl)vinyl]azetidine;4-methylbenzenesulfonicacid

The compound was prepared in analogy to BB95 from tert-butyl3-[(E)-2-(2-fluoro-4-methyl-phenyl)vinyl]azetidine-1-carboxylate and4-methylbenzenesulfonic acid monohydrate. Colorless solid (87%). MS(ESI): m/z=192.2 [M+H]⁺.

Step a) 1-(Diethoxyphosphorylmethyl)-2-fluoro-4-methyl-benzene

The compound was prepared in analogy to BB206, step a, from1-(bromomethyl)-2-fluoro-4-methylbenzene and triethyl phosphite followedby silica gel chromatography on a 40 g column using an MPLC (ISCO)system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100).Colorless liquid (85%). MS (ESI): m/z=261.1 [M+H]⁺.

Step b) tert-Butyl3-[(E)-2-(2-fluoro-4-methyl-phenyl)vinyl]azetidine-1-carboxylate

The compound was prepared in analogy to example BB206, step b, fromtert-butyl 3-formylazetidine-1-carboxylate and1-(diethoxyphosphorylmethyl)-2-fluoro-4-methyl-benzene. Colorless oil(7%). MS (ESI): m/z=236.2 [M−56+H]⁺.

1-56. (canceled)
 57. A compound, wherein the compound is:

or is a pharmaceutically acceptable salt thereof.
 58. The compound ofclaim 57, wherein the compound is:


59. A pharmaceutical composition comprising the compound of claim 57, ora pharmaceutically acceptable salt thereof, and a therapeutically inertcarrier.
 60. A pharmaceutical composition comprising the compound ofclaim 58, and a therapeutically inert carrier.
 61. A method of treatinga neurodegenerative disease in a mammal in need thereof, comprisingadministering to the mammal an effective amount of the compound of claim57, or a pharmaceutically acceptable salt thereof.
 62. The method ofclaim 61, wherein the neurodegenerative disease is multiple sclerosis,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,traumatic brain injury, neurotoxicity, stroke, or epilepsy.
 63. Themethod of claim 61, wherein the neurodegenerative disease is multiplesclerosis, Alzheimer's disease, or Parkinson's disease.
 64. The methodof claim 61, wherein the mammal is a human.
 65. The method of claim 62,wherein the mammal is a human.
 66. The method of claim 63, wherein themammal is a human.